Abstract
Traditional medicine has played a key role in cancer treatment, particularly in developing countries where herbal remedies are extensively utilized. Ethnopharmacological knowledge has highlighted several medicinal plants traditionally used to treat cancers. However, only a fraction of these plants have undergone scientific evaluation to validate their anticancer potential. This review summarizes the ethnopharmacological use, preclinical studies, and clinical trial data of plant-derived compounds with anticancer properties. Preclinical investigations have demonstrated substantial cytotoxic activities of plant extracts and isolated fractions against various human cancer cell lines. For instance, extracts from Acokanthera schimperi, Clematis simensis, Euphorbia schimperiana, Kalanchoe petitiana, and Plumbago zeylanicum demonstrated potent activities across various cancer types, with IC50 values ranging between 0.086 and 6.37 μg/mL. Building on these preclinical findings, several plant-derived compounds have progressed to clinical trials. Curcumin from Curcuma longa is undergoing Phase II trial for advanced pancreatic cancer. Tea polyphenols and *indole-3-carbinol/3,3-diindolylmethane have shown efficacy in Phase II trials for multiple myeloma and breast cancer, respectively. Besides, epigallocatechin, lycopene, resveratrol (Polygonum, sulforaphane (Brassica oleracea), roscovitine/seliciclib, thymoquinone, piperine, Berberine and genistein are under Phase I–III trials. This review integrates ethnopharmacological knowledge, preclinical data, and clinical evidence, showing the key role of medicinal plants in anticancer drug discovery. While significant progress has been made, further studies are required to isolate, characterize, and elucidate the mechanisms of action of bioactive compounds. Bridging traditional medicine with contemporary research offers promising avenues for the development of novel chemotherapeutic and chemopreventive agents, advancing the fight against cancer.
Background
Cancer is a complex disease when cells multiply and spread abnormally without control. Cancer is very heterogeneous at the cellular and patient level. Physical, metabolic, and behavioral variations of cancer cells from normal ones arise through the accumulation of genetic modifications, which help them to proliferate rapidly, escape from the host immune system, and invade distant organs. Histopathological, genetic, epigenetic, and clinical outcome differences between various cancer types are a major challenge in developing a new drug with a novel target. 1 Cancer is the main cause of death, which leads to a high health burden around the globe. The prevalence of cancers in the world for the year 2020 was 29.8 million cases, 19.3 million newer cancer cases and 10.0 million deaths reported. Lung cancer is the most prevalent (11.4%), then breast (6.9%), and colorectal cancer (10.0%) followed. Despite progress in drug development, Cancer is the world's second most prevalent cause of mortality. 2 It is responsible for 1 in every 6 deaths in the world, bearing 80% of the burden in terms of disability-adjusted life-years (DALYs). Unless more is done to change the path of the disease, this prevalence has a chance of over 30 million additional cases by 2040. In developing countries, the incidence of cancer is about 3 million with mortality of nearly 2 million. Currently, even if the incidence in developing countries is three times lower than in developed countries, more than half of the mortality from cancer occurs in developing Countries. 3
In Ethiopia, about 80,334 new cancer cases and 54,698 deaths were reported per year accounting for 5.8% of total national mortality. Breast, cervical, and ovarian cancers are the most common in females. But, bone and soft tissue, colorectal, and esophageal cancers in males.4,5 Most cancer cases are diagnosed at advanced stages that need chemotherapy. Drug cost, drug resistance, and availability of drugs are a barrier to cancer management especially in developing countries. 6 A study undertaken in Ethiopia among 1298 cancer patients only 1.4% got access to chemotherapy; even if most patients had an advanced stage that need chemotherapy. 7
Surgery, radiation, and Chemotherapy were means of treatment to control cancer. However, most chemotherapeutic drugs face difficulty and need alternative solutions because of increasing cancer deaths, lack of effective therapies, drug resistance, and severe side effects. The drugs derived from natural resources including plants, marine organisms, microorganisms, and their derivatives account for 60% anticancer agents. 8 Bioactive compounds derived from medicinal plants present a promising alternative source for effective anticancer drugs, often exhibiting improved adverse reaction profiles. With structural diversity, varied conformations, and complex steric arrangements, these compounds can support multiple biological functions essential for organism survival. Compared to synthetic organic compounds, bioactive compounds feature more chiral centers, fewer heteroatoms, and a lower presence of heavy atoms, while still maintaining “drug-like” properties. Over the past five decades, these attributes have fueled the development of natural anticancer chemotherapeutics, especially those sourced from microbes and higher plants. 9 Since the 1940s, anticancer drugs introduced in North America, Europe, and Japan have shown that approximately 47% of the 155 anticancer drugs approved by 2006 were either natural products or derived from natural sources. 10
In the past 20 years, pharmaceutical companies have scaled back research on natural products for new drug development. This shift largely stems from a strategic focus on rapid high-throughput screening of pure compound chemical libraries targeting specific molecular sites. Additionally, isolating bioactive compounds from crude extracts is often time-consuming and labor-intensive, further contributing to the decline in natural product research. 11 Currently, advanced technologies are enhancing the development of drugs from natural products within industrial settings. These advancements are expected to increase the role of natural products in future anticancer drug discovery. In fact, several new anticancer agents of natural origin have recently been approved for therapeutic use, with many others currently undergoing clinical trials. 12
The plant-derived anticancer agents are classified into four major groups: the vinca alkaloids (vinblastine, vincristine), the epipodophyllotoxin lignans (podophyllotoxin), the taxane diterpenoids (paclitaxel), and the camptothecin quinoline alkaloid derivatives (camptothecin). The vinca alkaloids and taxanes act on microtubulin with different mechanisms.12,13 Thus, Vinca alkaloids bind and disrupting microtubule assembly during mitosis, while taxane diterpenoids prevents the breakdown of microtubules during cell division. Camptothecin and its analogs, irinotecan and topotecan, inhibit topoisomerase I activity, arresting the cell cycle at the S-phase and thereby blocking DNA replication and transcription. 14 Podophyllotoxin binds to tubulin and interferes with the formation of spindles in mitosis. In contrast, the two clinically used derivatives of podophyllotoxin, etoposide, and teniposide are topoisomerase II inhibitors, which arrest the cell cycle in the metaphase by stabilizing the covalent DNA-enzyme cleavable complex and inducing topoisomerase II-mediated DNA breakage. 15
Several medicinal plants are known to have medicinal properties. An estimated 70,000 plant species, from algae to trees are used to treat several disorders. The National Cancer Institute has studied about 35,000 plant species for potential anticancer effects via in vitro and in vivo screens. 16
The American National Cancer Institute sets the cytotoxicity criteria for crude extracts as an IC50 < 20 µg/mL or 10 µM after 48 or 72 h of incubation. The NCI also considers a crude extract with an IC50 of 30 µg/mL as promising anticancer agent. However, other researchers, such as Ayoub et al, regard a crude extract as effective if it exhibits cytotoxicity at concentrations up to 100 µg/mL. In in vivo testing, human cancer cells are grown within fibers implanted subcutaneously or intraperitoneally in immunodeficient mice. 17 This review collects all the available data about cancer therapy of medicinal plants so far studied by ethnobotanical surveys in Ethiopia. In this review, I have not included plants that showed low antiproliferative activity (ie, IC50 > 50 µg/mL .This review compiled and discussed the potential anticancer plants based on antiproliferative activity.
Traditional Medicines and Cancer
Herbal medicine is the world's oldest system of traditional medicine. The World Health Organization (WHO) defines it as the practice involving herbs, herbal materials, preparations, and products containing bioactive compounds or other plant materials, either alone or in combination. Herbal medicine is widely used across all societies, with diverse preparation methods and treatment practices globally.18,19 Bioactive compounds derived from herbs can inhibit cancer growth by modulating hormone and enzyme activities. Herbal medicine is generally regarded as safe and is associated with fewer complications. Many cancer patients use herbal remedies alongside chemotherapy to enhance its effectiveness and reduce adverse reactions. Those who incorporate herbal remedies often report improvements in clinical symptoms, quality of life, reduced side effects, and extended survival.20,21 Many bioactive compounds extracted from herbs have been reported to support the immune system in fighting cancer more effectively. While traditional healers in Ethiopia use numerous medicinal plants, most of these species lack scientific evidence for their anticancer effects. 22
Ethiopia's diverse ecological, soil, and climatic conditions contribute to the rich variety of its flora, which includes around 6500 to 7000 species, with 12%–19% being endemic. Through scientific validation of medicinal plants, drugs such as morphine (from Papaver somniferum), paclitaxel (from Taxus brevifolia), arteether (from Artemisia annua), aspirin (from Salix alba), tiotropium (from Atropa belladonna), digitoxin (from Digitalis lanata), and quinine (from Cinchona officinalis) have been developed.19,23 In Ethiopia, 80% of the human population depends on traditional medicine, and more than 95% of the preparations are made from plant origin.24,25
The Reason to Review Anticancer Medicinal Plants
The incidence of cancer is on the rise globally. The disparity in cancer survival between developed and developing countries mainly lies on two factors: the stage of its diagnosis and availability and access to chemotherapy. 2 The everincreasing occurrence of cancer and the severe side effects and limited efficacy of chemotherapy based on synthetic drugs shift the attention toward drugs of plant origin. 4 In Ethiopia, soil degradation, deforestation, drought, high rate of cultural and habitat destruction, and various anthropogenic activities are threatening the MPs. However, recent ethnobotanical studies have shown that TM is widely practiced in the country. 9 It is also claimed that cancer patients prefer TMs to conventional therapeutic approaches mainly due to its cultural acceptance and ease of access. The Ethiopian flora largely remained untouched with tremendous potential that could offer a lot in the fight against cancer. Traditional knowledge, chemotaxonomic information and random screening have been the main approaches for selecting plant species in anticancer drug research. 13 Therefore, systematic review of ethnobotanical studies reported from Ethiopia would help identify potential anticancer MPs as showen in Table 1. This will serve as a basis for initiating rigorous scientific investigations for the chemopreventive and anticancer attributes of the MP species most frequently used across the regions of Ethiopia. Such investigation would contribute to the global anticancer drug discovery effort.
List of Most Frequently Cited Anticancer Medicinal Plants from Different Parts of Ethiopia.
Anticancer Activity of Selected Plants and Their Phytochemical Constituents
Numerous studies have demonstrated that certain plants possess significant efficacy against multiple cancer types, highlighting their potential as complementary therapies. These selected plants have been chosen based on their documented in vivo and in vitro anticancer effects, showcasing their ability to inhibit tumor growth, induce apoptosis in cancer cells, and reduce metastasis as presented in Table 2. As the exploration of natural compounds continues, the promise of plant-derived substances in cancer treatment remains a vital area of investigation. As investigations continue, the understanding of how these plant-derived substances can be integrated into cancer treatment regimens will likely expand, offering new hope in the fight against cancer.
List of medicinal plants, part used, solvents used for extraction and cell lines for anticancer studies.
Aerva javanica
Aerva javanica is a prostrate shrub species in the Amaranthaceae family. It is an erect, highly branched perennial herb native to Africa and found in various regions worldwide. Known for its role in desert reclamation as a soil binder, this plant is also valued for its therapeutic applications in traditional medicine. 78 In Ethiopia, Aerva javanica, commonly known as Tobia, is traditionally used for cancer treatment. To treat breast cancer, the root powder is mixed with bat's blood and taken orally before breakfast. 79 A decoction made from the aerial parts of Aerva javanica is used to relieve toothache and gum swelling. While the seeds are used to alleviate headaches, a paste made from the flowers and leaves is applied to treat wounds and joint inflammation. The plant is also utilized in traditional medicine to address conditions such as gonorrhea, chest pain, diarrhea, hyperglycemia, and serves as a diuretic and demulcent. Additionally, it is used to reduce swelling and pain associated with kidney stones, dysentery, gonorrhea, and skin infections. 80 Several phytochemical constituents are isolated from this plant including tannins, steroids, lipids, triterpenes, flavonoids, saponins, alkaloids, carbohydrates, and glycosides. 81 Several biological screenings showed the several biological activities of A. javanica. A. javanica exhibited anti-bacterial, anti-fungal, smooth muscle relaxant, antioxidant, antiviral, antiplasmodial, antidiabetic activities, and anti-ulcer activities. 80 The crude methanol leaf extracts of A. javanica possesses an antiproliferative effect on human breast cancer cell lines (MCF-7 at a lower concentration (11.89 and 22.45 μg/ml). The induction of cytotoxicity and DNA fragmentation was dose-dependent, the increased concentration of extracts induced a higher rate of cellular damage (MTT and DNA fragmentation assay). 26
Asparagus africanus Lam
Asparagus africanus is an herbaceous, perennial species in the family of Asparagaceae and widespread in the drier parts of tropical Africa. 82 There are many ethno-pharmacological claims on various parts of the plant, such as treatment of impotence, wounds, diarrhea, and Malaria. 83 In addition, its root aqueous extract has been taken regularly as an anti-depressant and to ease childbirth, hypertension, cancer, and epilepsy, applied externally for treating chronic gout. Studies showed that the aerial parts of this plant used to treat stomach pain, headache, ease childbirth, and stimulate hair growth. leaf and stem preparation of this plant is also used for tuberculosis and candida infection. 84
In Ethiopia, it is commonly known by the local name “yeset kest”or “Kestencha”. The plant is used as a remedy for many diseases in traditional medicine, including peptic ulcer, headache, backache, stomach pain diarrhea, Malaria, breast tumors, headaches, pain, rheumatism, and chronic gout. 85 Various studies also showed that A. africanus plant extract has different biological activities such as anti-bacterial, sexual impotency, gonorrhea, and syphilis; hepatoprotective; and antimalarial and insecticidal repellent properties. In addition to this, A. africanus is used for pharmacological activities such as anti-diabetic, anti-protozoal, antimycobacterial, anti-inflammatory and analgesic, anti-fertility, anti-microbial, and anti-oxidant activities. The roots of the plant uses for tumor treatment. 86 The primary phytoconstituents thought to be responsible for the pharmacological effects of Asparagus africanus include saponins, flavonoids, and tannins, such as spirostanosides, gallic acid, furostanol, sapogenin, and lignin. Additionally, other studies have reported the presence of steroidal saponins, including stigmasterol and sarsasapogenin, in the roots of Asparagus africanus Lam.87,88 The bioactive compound gallic acid from Asparagus africanus has exhibited antineoplastic properties. Furthermore, asparaginase—an enzyme sourced from another species in the genus, Asparagus officinalis—has been identified as a potent antileukemic agent. Additionally, antitumor activity has been recorded for asparagamine A from another species, Asparagus racemosus. 88
Glinus lotoides
Glinus lotoides L. is a member of the Molluginaceae family and is considered a dietary vegetable in Africa and Asia. In Ethiopia, it is commonly known by its vernacular name, “Meterie” or “Amkin.” The seeds of Glinus lotoides are utilized as an anthelmintic, laxative, wound healer, antibacterial, and anti-diabetic agent. It is available in Ethiopia for both nutritional and medicinal purposes. 37 several studies showed that G. lotoides possess the anti-tumor, chemo-preventive, wound healing, anti-cholesterolemic, hepatoprotective, and anti-oxidant properties. 53
The seed extracts of Glinus lotoides were evaluated for the anticancer effect of the lung cancer cell line (Calu-3) using MTT assay. The result showed that methanol crude extract showed the highest anticancer activity with an IC (50) value of 29:7 ± 1:3 μg/mL. The methanol and n-hexane extracts showed differential IC50 responses in carcinoma cell lines (Calu-3 IC (50)= 29.7 and 79.8 µg/mL and Caco-2 IC(50) = 69.7 and 74.6 µg/mL, respectively) as compared to normal cell lines (MDCK IC(50) = 106.1 and 131.1 µg/mL and IEC-6 IC(50) = 134.0 and 128.5 µg/mL, respectively). Besides these extracts induced significant apoptosis in the cancer cells (p < 0.05) at 100 µg/mL. 89 The antitumor activity of Glinus lotoides evaluated against Dalton's ascitic lymphoma (DAL) in mice and the result showed significant mean survival time improvement in tumor bearing mice and peritoneal cell count. 90
Withania somnifera
Withania somnifera is a medicinal herb from the Solanaceae family. This plant has been used in traditional medicine to treat various disorders. It serves multiple purposes, including acting as a sleep inducer, anticancer agent, antidiabetic, aphrodisiac, immunomodulator, anti-inflammatory, anti-aging, antidepressant, anticonvulsant, and astringent. 91 Moreover, it can also treat bronchitis, asthma, ulcers, emaciation, fertility, reproductive health care problems, cough, epilepsy, eye infections, scabies, paralysis, chest pain, and typhoid disease. 92
W. somnifera is a rich source of chemical compounds, including withanolides, anahygrine, withananine, anaferine, withanine, β-sitosterol, tropanol, chlorogenic acid, somniferiene, cysteine, scopoletin, and somniferimine. These compounds play a significant role in its biological activities, particularly its anticancer properties. 93 W. somnifera possesses broad dimensions of pharmacological activities such as antioxidant, antibacterial, cardio-protective, antifungal, anticarcinogenic, anti-inflammatory, anti-stress, antiparkinson, antialzheimer, neura and physical health enhancer.41,93
Yang et al reported that the root extract of W. somnifera can inhibit the metastasis of breast cancer in rats. 94 Roy et al described the antitumor effects of W. somnifera against prostate tumors, noting that its use leads to the inactivation of Cdc2, resulting in cell death. This demonstrates the role of W. somnifera as a regulator of the G2/M phase of the cell cycle and its efficacy against prostate tumors. 43 The leaves extract of W. somnifera were evaluated for their effects on the lung cancer cell line (NCI-H460), yielding an anticancer effect with an IC50 value of 0.45 μg/mL. Rai et al reviewed current studies, formulations, and future perspectives regarding the anticancer properties of W. somnifera. 61
Jatropha curcas
Jatropha curcas is a drought-resistant large shrub, which is cultivated in Africa and Asia for the production of biodiesel and medicinal purposes. The plant belongs to the family Euphorbiaceae, known for its’ toxic constituents. 95 There are numerous medical applications for J. curcas. It possesses Antihypertensive, Antiinflammatory, Antioxidant, Antineoplastic, Analgesic, Antidiarrheal, and Anti-bacterial activities that were found on this planet. 38 The ethnomedicinal uses of J. curcas have been documented in numerous countries across Africa, Asia, South America, and the Middle East, addressing nearly 100 different ailments. A paste made from the seed powder of the plant mixed with honey is utilized in tumor treatment. The seeds are employed for their purgative effects and in the treatment of syphilis. The leaves are used to address mouth infections, fever, jaundice, guinea worm sores, and joint rheumatism. Additionally, the roots of J. curcas, after being decocted, are used as a mouthwash for bleeding gums and to treat eczema, toothache, ringworm, scabies, dysentery, and venereal diseases such as gonorrhea. 96
In Ethiopian traditional medicine J. curcas (in Amharic yefernj gulo) is used to treat skin infection, infantile tetanus, dropsy, sciatica, paralysis, wound healing and some forms of tumor. The leaf is used in jaundice, as a mouthwash, in convulsion, and as an anti-helmintic agent; and the seed is used as a purgative, abortifacient, and contraceptive agent. 79 Phytochemical studies on J. curcas resulted in the isolation of many compounds including diterpenes, sterols, flavonoids, jatropholone A, jatropholone B, jatropholol alkaloids, triterpenes, ∝-amyrin and taraxerol; and the diterpenes, jatrphol, and phorbols. Curcin is a toxic protein extracted from the seeds.97,98
Most of these compounds exhibit a range of biological activities, from antimicrobial to anticancer effects. Curcusone A and B, Curcin, Caniojane, and Jatropholone (A and B), isolated from various parts of the plant, have demonstrated anticancer properties. In another study, extracts from the seeds, stem bark, roots, and leaves of J.curcas showed significant inhibitory effects against different cell lines, both in vitro and in vivo. Many of these compounds displayed strong cytotoxicity, with IC50 values ranging from 0.084 to 20.6 µM against HL-60, SMMC-7721, A-549, MCF-7, SW480, and HEPG2 cell lines.96,98
Rumex abyssinicus
Rumex abyssinicus is a flowering plant (genus: Rumex, family: Polygonaceae) native to tropical Africa. In Ethiopia, R. abyssinicus (makmeko in Amharic) has a wide spectrum of ethnomedicinal uses. The roots of the plant are commonly used as a cosmetic agent by Ethiopian women for dying the palms of the feet and hands. 82 In Ethiopia, it is also used to treat fevers, bacterial and fungal infections, hepatitis, hypertension, breast cancer, tuberculosis, jaundice, asthma, malaria, gonorrhea, constipation, neuralgia, rheumatism, migraine, rabies, scabies, wounds, typhus, headaches, vomiting, stomachaches, pneumonia, and diabetes mellitus.99,100
Studies have demonstrated that crude extracts of R. abyssinicus exhibit antibacterial, antifungal, anticancer, antiviral, anti-inflammatory, antioxidant, wound-healing, antimalarial, diuretic, analgesic, anti-Alzheimer's, anti-trypanosomal, and hepatoprotective properties. Analysis of the chemical constituents of R. abyssinicus has resulted in the isolation of anthraquinones, flavanols, terpenes, fatty acids, and organic acids. 101
Several studies have reported that root extracts of R. abyssinicus exhibit anticancer activity in tumor cell lines of the prostate, brain, breast, and leukemia. Worku et al investigated the in vitro anticancer effects of methanol extracts from R. abyssinicus rhizomes, finding an IC50 value of 3 μg/mL in human prostate cancer cells (LNCaP), leukemia (THP-1), and human astrocytoma cells (1321N1). The lowest IC50 observed was 2.4 μg/mL in LNCaP prostate cancer cells, while the highest inhibition constant recorded in PC-3 cells was 66 μg/mL. 102 Girma et al investigated the effects of methanol extracts from R. abyssinicus rhizome on dimethylhydrazine (DMH)-induced colon carcinogenesis in rats to assess in vivo chemopreventive activity against colon cancer. They reported that extract doses of 250 mg/kg and 500 mg/kg significantly reduced the occurrence of aberrant crypts (ACs) and aberrant crypt foci (ACF). 103
Myrtus communis
Myrtus communis L. (MC) is an evergreen shrub from the Myrtaceae family. Traditionally, it has been used to treat numerous conditions, such as diabetes, headaches, skin diseases, nosebleeds, leucorrhea, diarrhea, hemorrhage, urethritis, peptic ulcers, palpitations, hemorrhoids, inflammation, excessive sweating, conjunctivitis, and various pulmonary disorders, including cancer. The fruits of Myrtus communis are known for their anti-inflammatory, antinociceptive, antimicrobial, hypoglycemic, antimutagenic, and antioxidant properties. 104 The most common compounds available in Myrtus communis leaves, stems and flowers are α-pinene (∼10-60%) and 1,8-cineole (∼12-34%).22 Phenolic acids, components of M. communis L. extracts are garlic, ellagic, caffeic, syringic, vanillic, and ferulic acid. Flavonoids found in myrtle extracts are myricetin, quercetin, catechin, and their derivatives. 105 The hydroalcoholic leaves extract of Myrtus communis showed the highest anticancer activity against human colorectal cancer cell line, HT-29 with IC50 value of 8.2 µg/mL in WST-1 assay. 106 The ethanolic leaf extract of Myrtus communis demonstrated potent anticancer effects against various cancer cell lines, including breast (MCF-7), liver (HepG2), cervix (HeLa), and colon (HCT116) cells, with IC50 values of 83 ± 2.5 μg/mL for HCT116, 53.3 ± 0.6 μg/mL for HepG2, 41.5 ± 0.6 μg/mL for MCF-7, and 33.3 ± 3.6 μg/mL for HeLa. The extract induces apoptosis by arresting cells in the G1 phase of the cell cycle. In another study involving mice injected with Ehrlich ascites tumor cells, the water extract of M. communis was found to cure the animals when administered alongside the ascites cells. While the control animals with Ehrlich ascites tumors died approximately 19 days after injection, the extract-treated mice survived, and the study was concluded on the 29th day. 107
Various Myrtus communis extracts have been tested against different cancer cell lines, revealing that myrtucommulones, which contain a phloroglucinol core, exhibit cytotoxic effects on these lines. Myrtucommulone-A, a non-prenylated acylphloroglucinol, induces apoptosis in several cancer cell lines, including PC-3 (androgen-independent prostate carcinoma), LNCaP (androgen-dependent prostate carcinoma), KFR (rhabdomyosarcoma), HL-60 (acute promyelocytic leukemia), MM6 (acute monocytic leukemia), H9 (cutaneous T-cell lymphoma), DLD-1 (colorectal adenocarcinoma), and Jurkat (acute T-cell leukemia) through the mitochondrial cytochrome c/Apaf-1/caspase-9 pathway. 108 Essential oils of Myrtus communis were reported for the presence of 1,8-cineole, linalool, myrtenyl acetate, and myrtenol, which is responsible for its anticancer activity against blood cancer (leukemia). 109
Ocimum basilicum
Ocimum basilicum is an essential oil crop and medicinal herb that belongs to the Lamiaceae family. It is traditionally used to treat various diseases including asthma, cough, gastrointestinal disorders, cardiovascular diseases neurocognitive disorders, metabolic disorders tuberculosis, and acute lung diseases. 110 Infusions of Ocimum basilicum exhibit significant antioxidant, antimicrobial, anti-inflammatory, antidiabetic, and anticancer activities, as well as enhancing the phagocytic activity of neutrophils and providing immunostimulant effects. This plant contains various chemical compounds, including linalool, estragole, methyl cinnamate, 1,8-cineole, methyl chavicol, eugenol, bergamotene, α-cardinol, limonene, geraniol, and camphor. The flavonoid component enhances the phagocytic activity of neutrophils, while linalool demonstrates antimicrobial properties by inhibiting all tested microorganisms. 111 The highest inhibition of cancer cell growth was observed in the SKOV-3 cell line at a concentration of 5 mg/mL after 72 h, resulting in an IC50 value of 0.91 ± 0.11 mg/mL and a 91% reduction in cell growth. In contrast, the maximum cytotoxic effect of O. basilicum on AGS cells occurred at the same concentration (5 mg/mL) within 72 h, with an IC50 value of 3.18 ± 0.02 mg/mL and a 78% inhibition of cell growth. Zarlaha et al reported that the methanol extract of O. basilicum exhibited cytotoxic effects on MCF-7 cancer cells, while the ethanol extract demonstrated cytotoxicity against HeLa and SKOV3 cancer cells. 112
The in vitro cytotoxic activity of essential oils of Ocimum basilicum on human cervical cancer cell line (HeLa), human laryngeal epithelial carcinoma cell line (HEp-2), and NIH 3T3 mouse embryonic fibroblasts and the IC50 values obtained were 90.5 and 96.3 μg/mL, respectively. The protective effect against carcinogenesis of essential oils from basil leaves on Swiss mice with induced neoplasia was shown by the significant increase of the glutathione-S-transferase activity. caffeic acid, eugenol, isoeugenol, and rosmarinic acid are the major phytochemicals and therefore may be responsible for the anticancer activity against human cervix adenocarcinoma HeLa cells, human melanoma FemX, human chronic myelogenous leukemia K562. 113
Plambago zeylanicum
Plambago zeylanicum is a species of evergreen shrub belonging to the Plumbaginacea family. In Ethiopia, it grows in most parts of the country. it is known by the local name Amerra. In Ethiopian traditional medicine, this plant is used for the treatment of tonsillitis, abdominal colic, eye disease, TB, toothache, and cancer/tumor. As a remedy for cancer, the juicy product of squeezed fresh leaves is taken orally by patients suspected of having the disease. 114
Plumbago zeylanica L. contains a wide range of phytoconstituents like flavonoids, alkaloids, glycosides, saponins, steroids, tannins, triterpenoids, chitranone, isozeylanicone, zeylanicone, elliptinone, droserone, plumbagin, coumarins and phenolic compounds. These compounds have a broad range of pharmacological activities, which include antimicrobial, antihyperlipidemic, antiulcer, hepatoprotective, hair growth promoter and regulation
Solanum nigrum
Solanum nigrum is an annual herb that belongs to the Solanaceae family There are several species of the genus in Ethiopia which share the same local name- embuay/zerech embuay. The different parts of Solanum nigrum are reported to be eaten as food in different rural communities of Ethiopia. In addition, the leaves, roots, and stems of the plant are used for the treatment of various diseases including stomachache, inflammatory, diuretic effects, skin allergy, anthrax, gonorrhea, rabies, and cancer. 118 In support of the reported anticancer effects, the leaves of the plant have been demonstrated experimentally to inhibit the growth of cervical carcinoma in mice. Solanum nigrum contain the compound solanines, solasonine, solamargine, and solasodine which has potent antineoplastic activity, supporting at least the claimed anticancer activity of the plants used in Ethiopia. 25
The ethanolic extract of S. nigrum has exhibited in vitro inhibitory effects on melanoma cells. An in vivo study of a 1% aqueous extract of S. nigrum significantly reduced tumor mass in mice, achieving a tumor inhibition rate exceeding 50%. Additionally, it effectively inhibited lung metastasis in melanoma 119 Further studies showed that S. nigrum exhibits inhibitory effects on gastric, hepatocellular, and lung cancer. Notably, uttroside B, a saponin isolated from S.nigrum, showed a significant effect in liver cancer over sorafenib. S. nigrum effectively inhibits cancer cells, reverses drug resistance in tumors, and reduces the stemness of tumor stem cells. The antitumor effects of S. nigrum are done by inhibiting cellular proliferation, cell cycle arrest, induction of apoptosis, inhibiting tumor metastasis, reversing drug resistance, and enhancing the efficacy of radiotherapy and targeted therapy. 25
Cucumis prophetarum
Cucumis prophetarum is a species of tendrilbearing herb in the Cucurbitaceae family. It is commonly known by the name yemdir embuay in Ethiopia. Cucumis prophetarum has been used in traditional Ethiopian medicine as a remedy for several conditions including coughing, rabies in dogs, stomach pain, abortion induction, toothache, bad breath, diarrhea, gonorrhea, TB, and skin cancer. 120 Different parts of the plant are used for treating different types of disorders. For example, skin cancer is treated by pulverized roots made as pastes/ointments. Consistent with the reported anticancer claim in Ethiopia, scientific studies have also demonstrated potent antineoplastic activity for some compounds isolated from the fruits of the plant. Previous studies of the fruits of C. prophetarum isolated cucurbitacin (B, E, I, O, P and Q1), dihydrocucurbitacin (B, D and E), isocucurbitacin (B, D and E) and dihydroisocucurbitacin (D and E). cucurbitacin and its analogues have several pharmacological properties, including anticancer, antitumor, antipyretic, analgesic, anti-inflammatory, and hepatoprotective effects. 121 The diversity of cucurbitacin activities, especially differential cytotoxicity toward renal, brain, tumor, and melanoma cell lines, makes them potential species for further exploration. 122 The antiproliferative activity C. prophetarum leaf extract was evaluated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay on selected cancer cell lines. The IC50 values on A549, MDA-MB-231, HepG2, and MCF-7 were 105.8, 81.1, 94.2, and 65.6 μg/mL respectively. 122 The fresh fruit of Cucumis prophetarum isolation of five cucurbitacin compounds which showed cytotoxic activity against MCF-7, MDA MB 231, A2780, A2780 CP, HepG2, and HCT-116 with IC values ranging from 1 to 27.3 µM. 68
Prunus africana
Prunus africana is an evergreen tree within the Rosaceae family. The plant requires a moist climate to flourish and it grows well in many parts of Ethiopia, where it is commonly known by the local tikur enchet
P. africana possesses several bioactive compounds, including β-amyrin, N-butylbenzene-sulfonamide, β-sitosterol, β-sitosterol-3-O-glucoside, ferulic acid, tartaric acid, oleanolic acid, lauric acid, and ursolic acid. In vivo studies, mice with transgenic adenocarcinoma in their prostate were treated with P. africana and reported a significant decrease in prostate cancer when compared to the control group. In vivo studies, P. africana bark extracts induced 50% inhibition of the growth of human prostate cancer (PC-3). 124 It also elicited notable apoptosis in vitro in the PC-3 cell line. The presence of β-Sitosterol attributed to induces apoptosis in human prostate cancer cells. Also, the 2, 3-dihydro-3, 5-dihydroxy-6-methyl-4H-pyran-one in the extracts inhibit NF-kB which contributes to its proapoptotic and antiproliferative activities on PC-3 cancer cells. Besides, the presence of benzoic acid in the extracts may be responsible for anticancer as earlier studies showed that derivatives of benzoic acid hinder the growth of prostate cancer cells thus precluding oncogene expression by the inhibition of histone deacetylases. 125
Euphorbia tirucalli
Euphorbia tirucalli is a plant species in the family of Euphorbiaceae. it is distributed in Africa, mainly in the northeastern part of the continent including Ethiopia. It is commonly identified as kinchib in Ethiopia. The plant grows well in semi-arid tropical climates. 88 E. tirucalli produces milky vesicant/poisonous latex that contributes to its medicinal value. Latex of E. tirucalli is a vesicant and rubefacient, which is used in folk medicine for the treatment of rheumatism, warts, cough, asthma, ear-ache, tooth-ache syphilis, arthritis, cancer, and neuralgia. it acts as a purgative agent in small doses while at high doses it is bitter, irritant, and emetic. 126
The main bioactive compounds present in E. tirucalli latex are cyclotirucanenol (triterpene), diterpene ester, steroids, and tirucalicine (diterpene). Its active components include euphol, euphorbol, euphorone, isoeuphoral, taraxasterol, tirucalol, citric acid, glucose, kamepferol, malic acid, sapogenin acetate and succinic acid. 127 The main constituent of E. tirucalli sap is euphol, a tetracyclic triterpene alcohol, which has shown anti-inflammatory, antiviral, and analgesic properties. The bioactive components available in this plant showed biological activities, such as preventive anticancer activity, antitumor, antimutagenic, antibacterial, laxative, antiseptic, disinfectant, anti-inflammatory, antistreptococcal, antiparasitic, antiulcer, analgesic, antiasthmatic and expectorant properties, as well as anticancer effects against specific types of cancer of the breast, lung, cervix, esophagus and mouth. 126
Treatment of cancer by 0.5% solution of E. tirucalli 30 cH reported a 32.1% reduction in cell proliferation. Cytotoxic effects of high dilution of latex against MelanA (Non-tumoral melanocytes) and MCF-7 (Breast Carcinoma) cell lines were studied using MTT and May-Grunwald-Giemsa assays. Ethanol extract of stem bark of E. tirucalli was studied for its inhibitory activity by Patil and Mugdum where it showed effective inhibition.
Brucea antidysenterica
Brucea antidysenterica is a species of flowering shrub/tree in the family of Simaroubaceae that grows in Ethiopia. In Ethiopia, B. antidysenterica is commonly known as waginos or aballo. Different parts of the plant have been used to treat several diseases, including leprosy, wounds, diarrhea, fever, malaria, eye disease, amoeba, and rabies. 128 For cancer/tumor treatment, pastes made from leaves and young twigs with water are reported to be used topically. In Ethiopia, pastes made from powered leaves and young twigs with water have been used for the treatment of tumors, and a follow-up investigation showed that the plant has promising activity in vitro against several lymphoma, leukemia, and myeloma cell lines. 129 phytochemical investigations of the root and bark of B. antidysenterica led to the identification of Seven quassinoids including brusatol, bruceine D, bruceine H, yadanzioside A, yadanzioside G, javanicoside C, and bruceantinoside A.. Its root and bark extracts showed cytotoxic effects against PC-3 (prostate), A-549 (lung), and MCF-7 (breast) cancer cell lines. 72
Several studies showed that many quassinoids such as brusatol, bruceine D, and bruceine H possessed significant anticancer effect against pancreatic cancer cell lines (PANC-1, SW1990, CAPAN-1). Among them, brusatol showed the most potent in vitro antipancreatic cancer effect with (IC50) values of 0.36 μM and 0.10 μM on PANC-1 and SW1990 cell lines, respectively. 130 The two quassinoid compounds (bruceantin and bruceantinol) were found to possess strong antileukemic, or antineoplastic activity in cell and/or animal models. However, further phase 2 trials did not show the expected results to precede the trials. However, other research works showed that bruceantin was effective against leukemia, lymphoma, and myeloma cell lines in animal models with advanced stages of the disease. Studies showed that treatment of HL-60 and RPMI 8226 cell lines with bruceantin induced apoptosis by involving the caspase and mitochondrial pathways. Besides, in vivo study using RPMI 8226 human-SCID xenografts showed that bruceantin induced regression in early and advanced tumors. The mechanism of bruceantin associated with anticancer activity is inhibition of protein synthesis via interaction with peptidyltransferase, which blocks the formation of peptide binding. 131
Kalanchoe petitiana
Kalanchoe petitiana is a species of succulent plant that belongs to the family Crassulaceae. K. petitiana is native to Ethiopia and here it is commonly called indahula. Different parts of the plant are used to treating many disease conditions in Ethiopian traditional medicine. These conditions include epilepsy, trachoma, allergy, intestinal parasites, gonorrhea, malignant wounds, breast tumors, and skin cancer. 131 The leaves of the plant are used for treating breast and skin cancer in Ethiopian traditional medicine practice. Confirming the anticancer effect reported, gallic acid with potent antitumor activity has been isolated from the leaves of K. petitiana. The gallic acid isolated from the leave of Kalanchoe petition is responsible for its anticancer activity. 88 K. petitiana showed promising cytotoxic activity with IC50 values ranging from 2.09 ± 0.43 to 10.41 ± 5.59 µg/mL. 49
Crinum abyssinicum
Crinum abyssinicum Hochst. ex A is a bulbous plant that belongs to the family of Amaryllidaceae. This plant prefers a sunny condition on fresh to moist soil to grow well. Crinum abyssinicum locally known as “yejib shinkurt” in Amharic. It has been found in Ethiopia's most floristic regions, but it is unknown outside of the Horn of Africa. In Ethiopia, different components of Crinum abyssinicum are traditionally used to treat several diseases, including wounds, hypertension, diabetes, hepatitis B, skin infection, and several types of tumors. The root part have been used for treatment of hepatitis, and hemorrhage, leaves for skin infection, swelling, and cancer; the roots and bulbs have been used for snakebite and earache; bulbs for rheumatoid and evil spirits. 132 Several studies revealed that C. abyscinicum contain compounds including lycorine, crimine, narciclasine, 3-epihalmanthidine, crinamine, lycobetaine precriwelline, crinamide, crinafolidine, criasbetaine, crinasiadine, crinasiatine, and crotepoxide.
Among these compounds, 6-hydroxycrinamine and lycorine showed Promising antiproliferative activity against A2780 epithelial ovarian cancer and MV4-11 acute myeloid leukemia cell lines. They promote cell cycle arrest in A2780 cells without inducing apoptosis. 73 6-Hydroxycrinamine was also reported to be cytotoxic against human pancreatic (PANC1, IC50 = 7.20 μg/ml) and prostate (DU145, IC50 = 2.95 μg/ml) cancer cells. 133 Lycorine also showed in vitro anticancer effect against ovarian carcinoma cell line (SK-OV-3) with an IC50 value of 0.86 μg/ml. Lycorine showed inhibitory effect against different cancer cell lines including lymphoma, melanoma, leukemia, lung cancer, esophageal cancer, and human anaplastic oligodendroglioma. 134
Gloriosa superba
Gloriosa superba is a species of perennial trailing/climbing herb belonging to the family Liliaceae. G. superba is a toxic plant due to the presence of an alkaloid, ‘Colchicine’. Gloriosa superba is a traditional medicinal plant for treating various diseases. In Ethiopia, this plant species is called Etse Lebona. G. superba roots have been used to treat stomachache and breast cancer when chewed and applied externally on location, respectively. 88 G. superba is utilized for the treatment of snakebite, scorpion stings, parasitic skin disease, urological pains, colic, chronic ulcers, piles, gonorrhea, gout, infertility, wounds, arthritis, cholera, kidney problems, itching, leprosy, cancer, sexually transmitted disease, and countless other diseases. 135 The flower has analgesic, anti-inflammatory potential, antimicrobial, larvicidal, anti-poxviral, antithrombotic, and antitumor activity. This plant is used to treat snake bites and respiratory disorders.
Photochemical studies of G. superba shows presence of colchicin, gloriosine, 3-desmethyl colchicine, β-lumicolchicine, 2-desmethyl colchicine b-siltosterol, long chain fatty acids luterlin, N-formyl-deacetyl colchicines and new colchicine glycoside, 3-O-demethylcolchicine-3-Oalpha-D-glucopyranoside. FDA-approved use of Colchicine is to treat gout. It is also used as an anticancer, antimicrobial, antifungal, anticoagulant, antilipoxygenase agent and antidote in snake bite. 136 Colchicine arrest mitosis and induces apoptosis of colon cancer cells. Colchicine inhibits proliferation due to its ability to bind to the ends of microtubules and block microtubule elongation. Colchicine inhibits colon cancer cell growth by inducing caspase-3-promoted cell death. 137 The cytotoxic activity of Gloriosa superba methano extract Linn on HELA and MCF7 cell lines showed the IC50 197.06 µg/mL and 199.45 µg/mL, respectively. 138
Lagenaria sicararia
Lagenaria sicararia is a climbing plant that belongs to the Cucurbitaceae family. The plant has been used for many purposes, primarily to provide food, medicine, and utility objects. The plant parts of used to treat various diseases such as asthma, fever, hypertension, jaundice, cardiac, bronchial, and skin problems. In addition, it is used as diuretic, emetic, purgative, sedative and cardiotonic agent. It also possesses several therapeutic properties such as antidote, antidiabetic, aphrodisiac, antioxidant, anti-inflammatory, analgestic and cardioprotective. 139
Ascorbic acid, triterpenoid, minerals, choline, amino acids, vitamin-B complex, triterpenoid cucurbitacins B, D, H, G, 22-deoxy cucurbitacin, β-glycosidase-elastase, flavonoids, sterols, and carbohydrates are all found in the edible part of the fruit. In Ethiopia, It is used as a traditional medicinal plant for treating otitis media, mental illness, and cancerous sores. To treat cancer, the leaves are crushed and squeezed onto the affected body part. Complying with this, there is scientific evidence that alcohol extracts and some triterpinoid compounds isolated from the stems and fruits of L. sicararia exhibit significant cytotoxicity and anticancer activities against SKHIP1 cell line and human breast carcinoma cell line (MCF-7).88,140 The extract showed dose-dependent inhibitory and cytotoxicity against tested cell lines. The bitter component of L. siceraria displayed the highest toxicity against cancer cell line MCF-7 with GI50 < 10 μg/mL but considerable cytotoxic activity against the HT-29 cell line. 139 The methanolic Extract caused a significant decrease in the proliferation of lung cancer cell line (IC50 = 93.094 ± 6.5 μg/ml. 141
Podocarpus falcatus
Podocarpus falcactus, also known as Afrocarpus falcactus “Zigiba” in Amharic, is an Indigenous evergreen species of coniferous tree in the family Podocarpaceae, commercially known as the East African yellow wood. It is found in mountain forests and is native to eastern Africa; in Ethiopia, Kenya, Tanzania, Uganda, and Mozambique. Podocarpus falcactus is used in traditional medicine to treat fever, asthma, cough, cholera, chest complaints, hepatitis, venereal disease, vomiting, febrile illness, and inability to urinate. The stem bark extracts are used to treat stomachache, gonorrhea, deworming, and cancer. The gum and shoot parts are used for the treatment of diabetes, cough, lung problems, and vomiting. The shoot apex is crushed, mixed with water, and taken orally as a diuretic to treat unable to urinate. 142 It is traditionally used to treat jaundice, gastritis, and amoeba. Oils from Podocarpus falcatus are used for treating gonorrhea and bark is used for curing headaches in Ethiopia. Phytochemical investigation of the leaf extract of the plant revealed the presence of polyphenols and diterpenoids, including podolactones (nor- and bis-norditerpenoid dilactones), abietane, sempervirol diterpenoids, flavonoids, and Quercetin-3-O-Glycoside or Quercetin-3-O-β-D-Glucopyranoside (QG) flavonol glycosides. The di-terpenoid taxol and polyphenols from the plant Podocarpus falcactus have shown potent antioxidant activity.77,143 Podocarpus falcactus leaves showed antioxidant and antimicrobial, activities. It also has a cytotoxic effect against breast adenocarcinoma cell lines. Even the known anticancer drug taxol is found in Podocarpus falcactus extract. Addo et al isolated two new additional nagilactones along with seven already known from the root of Podocarpus falcatus (Thunb.) collected from central part of Ethiopia. Among the isolated compounds 16-hydroxynagilactone F, 2β,16-dihydroxynagilactone F, 7β-hydroxymacrophyllic acid, nagilactone D, 15-hydroxynagilactone, and nagilactone showed potent antiproliferative activity against HT-29 cell line (IC50 < 10 µM). 77
Clinical Anticancer Potential of Phytochemicals
Clinical studies involving phytochemicals are currently emphasizing three key areas in cancer research: enhancing cancer cell responsiveness to chemotherapy and radiation, minimizing the severe side effects associated with standard cancer therapies, and identifying any potential adverse interactions with these therapies. Preclinical studies have demonstrated the efficacy of various phytochemicals, including lycopene, quercetin, resveratrol, curcumin, berberine, sulforaphane, and catechins from green tea. Ongoing clinical trials are investigating the anticancer potential of these phytochemicals as shown in Table 3.
Phytochemicals Evaluated in Clinical Trials.
Several clinical trials have investigated lycopene's efficacy in cancer treatment. A Phase II randomized clinical trial (ClinicalTrials.gov Identifier: NCT01226924) evaluated lycopene supplementation in patients with newly diagnosed, clinically localized prostate cancer. The study showed that a daily dose of 15 mg of lycopene was well tolerated and did not significantly increase side effects. However, the trial did not demonstrate a statistically significant reduction in cancer recurrence or mortality rates. Another clinical trial (ClinicalTrials.gov Identifier: NCT01338056) assessed the effects of lycopene supplementation on patients with benign prostate hyperplasia (BPH). The study reported that a 24-week intervention with lycopene supplementation (15 mg/day) resulted in a significant reduction in total prostate-specific antigen (TPSA) levels, a marker of prostate inflammation, suggesting potential benefits for individuals with BPH.
An ongoing Phase III clinical trial (ClinicalTrials.gov Identifier: NCT03697314) is currently evaluating lycopene's role in combination with standard treatments for patients with advanced colorectal cancer. Preliminary results indicate that lycopene supplementation may enhance treatment efficacy by improving tumor response rates and patient survival outcomes. However, further research is necessary to confirm these findings and establish optimal dosing strategies for lycopene in cancer therapy. These studies underscore lycopene's potential as a complementary therapy in cancer treatment. Additional research is warranted to clarify its mechanisms of action and establish its efficacy across different cancer types and patient populations.
A Phase II clinical trial (ClinicalTrials.gov Identifier: NCT01759755) investigated the effects of sulforaphane on prostate cancer patients, specifically assessing whether it could lead to a decline of ≥ 50% in prostate-specific antigen (PSA) levels. Twenty participants received 200 μmol/day of sulforaphane-rich extracts for 20 weeks, during which their PSA levels were monitored. While only one patient demonstrated a ≥ 50% decline in PSA levels, sulforaphane extended the PSA doubling time (PSADT) from 6.1 months prior to treatment to 9.6 months during treatment. PSADT serves as a critical indicator of prostate cancer progression, predicting the duration required for PSA levels to double."29,151
In a Phase II clinical trial (ClinicalTrials.gov Identifier: NCT01319424), SRT501, a formulation of resveratrol, was proven to be safe and did not cause nephrotoxicity in colorectal cancer patients, although such adverse effects were observed in patients with multiple myeloma. Furthermore, Roscovitine, a related compound, demonstrates a more selective cytotoxic effect toward cancerous cells compared to normal cells, exerting a potent pro-apoptotic effect through p53-dependent pathways. 153
In in vitro studies, piperine has demonstrated synergistic antiproliferative effects in the MCF7 cell line and enhances the efficacy of tamoxifen when combined with hesperidin and bee venom in both MCF7 and T47D cell lines. It reduced the LC50 value of paclitaxel from 50 μM to 25 μM, thereby decreasing the lag phase during the action time of paclitaxel in an in vitro MDA MB-231 cell line model. Piperine also augmented the cytotoxic and antiproliferative effects of paclitaxel and doxorubicin when used in combination. 155
In vivo, piperine, alongside thymoquinone, inhibited angiogenesis, induced apoptosis, and modulated the immune response towards T helper 1 in Balb/C mice inoculated with EMT6/P cells. A stem cell model for breast cancer showed that piperine, in combination with curcumin, inhibited mammosphere formation and the proliferation of aldehyde dehydrogenase (ALDH +) breast stem cells in both normal and malignant breast tissues, while also inhibiting Wnt signaling. Piperine induced apoptosis through the activation of caspase-3 and cleavage of Poly (ADP-ribose) polymerase (PARP), inhibiting HER2 gene expression at the transcriptional level. Furthermore, pretreatment with piperine enhanced the sensitization of HER2-overexpressing breast cancer cells to paclitaxel. In SK-MEL 28 and B16-F0 cell lines, piperine caused G1 phase cell cycle arrest and apoptosis by activating checkpoint kinase 1, followed by downregulation of XIAP, full-length Bid (FL-Bid), and cleavage of caspase-3 and PARP. Piperine–curcumin dual drug-loaded nanoparticles effectively targeted multidrug-resistant cancers, while guar gum microvehicles loaded with thymoquinone and piperine demonstrated low median lethal dose (LD50) values against human hepatocellular carcinoma cell lines. Notably, piperine-free extracts of Piper nigrum also exhibited anticancer effects on cholangiocarcinoma cell lines. 156 Moreover, piperine inhibited the proliferation of prostate cancer cell lines by reducing the expression of phosphorylated STAT-3 and nuclear factor-kB (NF-kB) transcription factors. Piperine-loaded core–shell nanoparticles resulted in significant alterations in cytotoxicity compared to free drugs, increasing G2/M-phase and pre-G1-phase populations, inhibiting CDK2a, and enhancing apoptotic and necrotic rates in the human brain cancer cell line Hs683. Piperine also inhibited cell cycle progression in rectal cancer cells through ROS-mediated apoptosis (ClinicalTrials.gov Identifier: NCT03127884). 157
Conclusion and Future Perspective
Medicinal plants represent a significant source for the discovery of new lead compounds, as illustrated by the promising findings in this review. Euphorbia schimperiana (LCLC-103H, IC50: 0.086 µg/mL) and Clematis simensis (MCF-7, IC50: 0.09 µg/mL) demonstrated exceptional anti-cancer efficacy, underscoring their potential as high-priority candidates for further investigation. Multi-target plants, such as Kalanchoe petitiana and Rumex abyssinicus, exhibited activity against multiple cancer types with IC50 values below 20 µg/mL, highlighting their versatility in addressing various malignancies. Furthermore, compounds like Lycorine and Cucurbitacins show considerable promise for targeted therapy.
Ethnopharmacological knowledge, complemented by interdisciplinary research, offers valuable insights that can streamline the identification of bioactive compounds and facilitate their transition from preclinical studies to clinical trials. However, challenges remain, such as the need for a deeper understanding of the molecular interactions of these compounds with receptors and signaling pathways. Molecular docking techniques, validated by robust in vitro and in vivo studies, can address these gaps. Extensive, well-controlled clinical trials are also essential to assess the efficacy and safety of these bioactive compounds.
Footnotes
Abbreviations
Acknowledgements
I would like to acknowledge Mrs Fasika Abu for editing the paper.
Authors’ Contributions
TM conceived the idea, drafted and revised the manuscript for intellectual content. The author read and approved the final manuscript.
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Department of pharmacology, College of medicine and Health Sciences, University of Gondar Tafere Mulaw Belete.
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