Abstract
Increase in cases of various cancers has encouraged the researchers to discover novel, more effective drugs from plant sources. This study is a review of medicinal plants in Iran with already investigated anticancer effects on various cell lines. Thirty-six medicinal plants alongside their products with anticancer effects as well as the most important plant compounds responsible for the plants’ anticancer effect were introduced. Phenolic and alkaloid compounds were demonstrated to have anticancer effects on various cancers in most studies. The plants and their active compounds exerted anticancer effects by removing free radicals and antioxidant effects, cell cycle arrest, induction of apoptosis, and inhibition of angiogenesis. The investigated plants in Iran contain the compounds that are able to contribute effectively to fighting cancer cells. Therefore, the extract and active compounds of the medicinal plants introduced in this review article could open a way to conduct clinical trials on cancer and greatly help researchers and pharmacists develop new anticancer drugs.
Introduction
Cancer is a main reason for mortality involving more than one-third of the global population in some way. Cancer is the cause of more than 20% of the whole mortality worldwide. 1 According to the report of the International Agency for Research on Cancer 2 of the World Health Organization published in 2014, the global incidence of cancer has been approximately 14 million new cases and is projected to register 19.3 million in 2025. According to this report, lung cancer was the most prevalent cancer (13%) in 2012 followed by breast cancer (11.9%), colon cancer (9.7%), and prostate cancer (7.9%). In Iran, the mean rate of cancer incidence has been 7.134 per 100 000 population, 85 000 individuals are estimated to acquire cancer and nearly 55 000 individuals die due to cancer per year. 2,3
Meanwhile, there are a variety of therapeutic approaches to treat cancer, including surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy. Despite being highly efficient, surgery is not always practical under any circumstances. For radiotherapy, systemic radiotherapy is variously conducted, including external radiation therapy, brachiotherapy, and internal radiation therapy in view of the source and site of tumor and the type of cells with several side effects, alongside therapeutic effect, for the patient such as poisoning as the most significant one leading to variation in skin health as alopecia and destruction of epithelial cells (scaling) and epithelial moisture (dermis revealing and skin secretion of serous fluid) and potentially mouth ulcers and complications, bone marrow suppression, and development of anemia, leukopenia, and thrombocytopenia. 4 Chemotherapy drugs, including antimetabolites (such as methotrexate), passive material of DNA (such as cisplatin and doxorubicin), antitubulin agents (such as taxis), and hormones that are most frequently used cause unwanted effects, including hair loss, bone marrow suppression, drug resistance, gastric ulcer, neurological dysfunction, and cardiac toxicity. 5 –7
In view of the above complications of the therapies currently considered for cancer, high costs of conventional therapies, and growing incidence of cancer in both developed and developing countries, it seems necessary to develop more novel approaches with higher efficiency so that the disease intensity could be declined. In this regard, there is considerable scientific and commercial interest in developing new anticancer agents from natural sources and the research aimed to develop new anticancer drugs has been turned into a significant research area. 8 In fact, naturally derived combinations have been under pharmacists’ focus to synthesize new drugs and treat diseases due to availability, less frequent side effects and drug interactions, and cheapness. 9,10
Plants produce a wide spectrum of chemical compounds with apparently no direct contribution to their growth and development, namely secondary metabolites. Terpenes, nitrogen-containing, and phenolic compounds are 3 main classes of these compounds with various biological properties in plants that are used for a wide variety of diseases including cancers, 11,12 neurological disorders, 13 chronic inflammation and lesions, particularly due to diabetes, 14,15 atherosclerosis, 16,17 cardiovascular diseases, 18,19 and wounds. 20 In addition, these natural products have been used alongside radiotherapy.
This article is a review of Iran’s medicinal plants that have been already examined for anticancer effects, and also seeks to offer their main compounds and mechanisms of anticancer activities. This review article could open a way to develop new anticancer drugs for prevention and treatment of cancers.
Materials and Methods
In this systematic review, to collect data, different combinations of keywords medicinal plants, anticancer, Iran, cytotoxicity, cell line, and phytochemical compounds and their Persian equivalents were entered into databases consisting of Magiran, SID, and Iran Medex, as well as, international databases of Web of Knowledge, PubMed, and Scopus. The articles only in English and Persian languages published between 1976 and March, 2015 were only searched. Then, the articles on application of Iran’s medicinal plants for prevention and treatment of cancers were selected, and those demonstrating anticancer effects of these plants and/or their compounds were reported.
Results
From the findings, 36 medicinal plants in Iran with studies conducted on their anticancer effects were reported (Table 1). Despite the fact that lung cancer has been the most prevalent cancer in 2014, little research has been conducted on the effects of medicinal plants on this cancer. Most studies have addressed breast cancer (Table 2). In most conducted studies, no clear mechanism of the plant effect has been offered. However, some compounds of the plants have been reported to be possibly responsible for anticancer effects. In addition, in some of the studies some compounds were extracted from the plants and the effect of these compounds on various cell lines were studied. Phenolic and alkaloid compounds were demonstrated to have anticancer effects on various cancers in most studies.
Anticancer Effects of Various Iranian Medicinal Plants.
Effect of Iranian Medicinal Plants on Different Cancers.
Discussion
The available therapeutic approaches to treat cancers are mostly accompanied with undesirable side effects (gastrointestinal disorders, kidney damage, etc). The present study indicated that the studied medicinal plants in Iran contain the compounds engaging specifically in fighting cancer cells and inhibiting growth and destruction of tumor cells only by affecting cancer cells.
These compounds mainly include alkaloids and phenolic and monoterpene compounds. Vinblastine, vincristine, curcumin, myrtucommulone, taxol, boswellic acids, and umbelliprenin, quercetin, catechin, cucurbitacin, kaempferol, thymol, carvacrol, 1,8-cineole, α-pinene, myrecene, β-sitosterol were some compounds with reported anticancer effects in most works. Alkaloids are nitrogen-containing compounds with plant origin, which often have a complex structure, high molecular weight, and show physiological activity in humans. Alkaloids cause cell cycle arrest in metaphase stage by preventing the formation of microtubules and hence could prevent cancer. 172
Cancers and most difficult-to-cure diseases are associated with high level of oxidative stress. 173 –175 Oxidative stress is a phenomenon which may cause damage to various physiological and biochemical processes. Overproduction of such free radicals may also cause oxidative damage to biomolecules such as DNA, lipids, and proteins. 176 –178 This process eventually may lead to many chronic diseases, including cancer, atherosclerosis, diabetes, aging, and other degenerative diseases in humans. 179 –181 Most of medicinal plants with anticancer property have antioxidant activity due to phenolic compounds. Therefore, these plants may, at least in part, exert their anticancer effects by counteracting free radicals. Antioxidant property of phenolic compounds (including flavonols and flavonoids) is due to the presence of hydroxyl groups. 182,183 Actually, medicinal plants with antioxidant activity play a crucial role in scavenging free radicals. They also are able to reduce the toxicity of toxic agents which induce oxidative stress. 184 –188 If this is true, other plants with antioxidant property are likely to have anticancer activity, which should be further investigated.
On the other hand, the ability to induce apoptosis is an important marker for cytotoxic antitumor agents. Studies have shown that cytotoxic effect of alkaloids and phenols against different tumors is mediated through apoptosis.
Phenolic compounds exhibit anticancer effects through affecting cell proliferation processes (eg, through the G2/M cell cycle arrest and inhibition of topoisomerase II), apoptosis, angiogenesis, and the impact on the routes of phosphoinositide 3-kinase (PI3-K) and protein kinase B (Akt). Studies have demonstrated that inhibition of PI3-K activity inhibits phosphorylation of Akt and mammalian target of rapamycin (mTOR), which leads to reduced activity of nuclear factor-κB (NF-κB). Through this mechanism, transcription and synthesis of the cell cycle-driving proteins are inhibited and thus the growth of cancer cells is reduced and the cell death increases. 189 –192 For example, quercetin, a phenolic compound in plants, prevents the activation of the transcription factor NF-κB through inhibiting Akt and Ikka-a phosphorylation and hence the anticancer activity is exerted. 193 Curcumin, as a major pigment in turmeric, induces apoptosis in transformed rodent and human cells in inhibition of the culture of formation of cyclooxygenase metabolite. 69 –72
Conclusion
The investigated medicinal plants in this article could be a key to identifying the compounds with anti-cancer effects; therefore, if their compounds are examined, they might help to develop new, more efficient drugs, in addition to contributing to identifying the main mechanisms involved in cancer.
Footnotes
Author Contributions
All the authors wrote the first draft of the manuscript equally. MAS and HS revised and edited the last version.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work has been extracted from the PhD thesis of Majid Asadi-Samani and it has been funded by Deputy of Research and Technology of Shahrekord University of Medical Sciences.
Ethical Approval
As this review did not involve any human or animal subjects, ethical approval was not required.