A Review of the Research Progress on the Anticancer Mechanisms of the Active Components Baicalin and Baicalein of Scutellaria baicalensis in Digestive System Tumors

Abstract

Gastrointestinal tumors are considerably heterogeneous and are associated with high incidence and mortality rates. Baicalin and baicalein are flavonoid compounds derived from the roots of Scutellaria baicalensis, a traditional Chinese medicinal herb with a longstanding history of therapeutic use. These compounds exhibit broad bioactivity, including antioxidant, antiviral, antibacterial, anti-inflammatory, and anti-allergic effects. The present review synthesizes evidence on the anticancer effects of baicalin and baicalein in digestive tract tumors, highlighting the underlying mechanisms. Baicalin and baicalein mediate their anticancer effects by inducing programmed cell death pathways, such as apoptosis and autophagy, halting cell cycle progression, and blocking tumor cell growth and metastasis. They also suppress tumor cell invasiveness, reverse drug resistance, and inhibit tumor initiation. Finally, relevant in vitro and in vivo experimental findings are discussed to support these mechanisms. Overall, baicalin and baicalein demonstrate considerable potential as novel therapeutic agents for the treatment of digestive system malignancies.

Introduction

In 2019, the World Health Organization revised the classification of digestive system tumors to encompass esophageal, gastric, colorectal (CRC), pancreatic, and hepatocellular carcinoma (HCC). ¹ Owing to their high incidence and mortality rates, these malignancies present a growing global health burden.^2–4 Existing therapies for gastrointestinal malignancies include surgical resection, radiotherapy, systemic chemotherapy, targeted agents, and immune checkpoint inhibitors. However, these approaches often fail to eradicate residual disease or prevent long-term tumor progression,^5–10 underscoring the urgent need for improved therapeutic strategies.

Scutellaria baicalensis Georgi, a member of the mint family, is a traditional Chinese medicine (TCM) with a history of use spanning over two millennia. It is officially recognized in the 2020 Chinese Pharmacopoeia, ¹¹ and its root is the principal medicinal part. Native to East Asia, S. baicalensis is now widely cultivated, with China being a major producer. In China, the plant is primarily distributed across the Northeast, North, Central, and Southwest regions, particularly north of the Yangtze River.^12,13 Traditionally, S. baicalensis has been used to clear heat, eliminate dampness, purge fire, and detoxify. It possesses anti-inflammatory and antiviral properties, promotes diuresis, reduces swelling, and restores internal balance. It has also been used in the treatment of various diseases, such as lung heat, cough, damp heat, diarrhea, and inflammatory lesions.

The therapeutic effects of S. baicalensis, are primarily attributed to its bioactive flavonoid constituents, including baicalin, baicalein (Figure 1), and structurally related compounds. Among them, baicalin and baicalein are the most extensively studied. Baicalein is a flavonoid compound with the molecular formula C₁₅H₁₀O₅, featuring three hydroxyl groups (-OH) and an enol derivative. Its core structure is a flavonoid skeleton containing an aromatic ring. ¹⁴ Both compounds exhibit pharmacological activities, including neuroprotective, immunomodulatory, hepatoprotective, antioxidant, antiviral, antibacterial, and antitumor effects. ¹⁵ Baicalin (C₂₁H₁₈O₁₁) is the glycoside form of baicalein, formed by the connection of baicalein with a glucose molecule through a glycosidic bond. Its defining structural feature is its glycosidic group, ¹⁶ which is hydrolyzed in the digestive system, releasing the smaller and more easily absorbed baicalein, which exerts a more direct antitumor effect within the body.^17,18 The glycosidic portion can influence the timing and intensity of the pharmacological effects, modify tumor cell uptake, and increase cellular absorption by binding to specific receptors on the cell membrane. It also enhances metabolic stability and improves antitumor efficiency. ¹⁹ Accordingly, the antitumor properties of S. baicalensis and its constituents have attracted increasing interest. A study on the efficacy of baicalin in gastric cancer indicated that baicalin exhibited significant inhibitory effects on gastric cancer cells, with a half maximal inhibitory concentration ranging between 10 and 50 µM. ²⁰ Moreover, baicalein exhibited a half maximal inhibitory concentration of approximately 30 µM in AGS cells (human gastric adenocarcinoma cells). ²¹

Figure 1.

Structures of baicalein and baicalin.

The present review synthesizes recent preclinical evidence on the anticancer effects of baicalin and baicalein in digestive system tumors, focusing on their underlying molecular mechanisms. This review aimed to explore potential novel TCM-based therapeutic strategies in gastrointestinal tumors.

Induction of Tumor Cell Apoptosis and Autophagy by Baicalin and Baicalein

Apoptosis

Cell death occurs via three principal modalities: apoptosis (type I), autophagic cell death (type II), and necrosis (type III). Among these, apoptosis is a controlled, ATP-requiring cell death program that occurs in both health and disease states. It is characterized by chromatin compaction, membrane blebs, cytoplasmic shrinkage, and DNA fragmentation. ²¹ Apoptosis plays a critical role in eliminating cancer cells and is mediated primarily through two pathways: intrinsic and extrinsic. ²² The intrinsic pathway is induced by cellular stressors, such as growth factor deprivation, ionizing radiation, reactive oxygen species accumulation, and endoplasmic reticulum (ER) stress. These stressors disrupt mitochondrial membrane permeability and activate the tumor suppressor protein p53, which in turn upregulates the expression of proapoptotic proteins, including BCL2-associated X protein (BAX) and BCL-2-associated death promoter, while inhibiting the expression of anti-apoptotic members of the B-cell lymphoma 2 (Bcl-2) family, including myeloid leukemia 1, Bcl-2, and Bcl-xL. This shift in balance between pro- and anti-apoptotic factors triggers the release of cytochrome c (Cyto-C) from mitochondria, activating the caspase cascade and driving the cell toward apoptosis. ²³ The extrinsic pathway involves death ligands, such as CD95, tumor necrosis factor-α (TNF-α), and TNF-related apoptosis-inducing ligand, which bind to their respective receptors to assemble death-inducing signaling complexes. ²²

In the following section, the potent proapoptotic activity of S. baicalensis in gastrointestinal tumor cells is summarized.

Induction of Apoptosis via Intrinsic and Extrinsic Pathways

Apoptosis is induced through both intrinsic and extrinsic pathways by the activation of the first apoptosis signal receptor (Fas) and caspases-2, −3, −8, and −9, along with upregulation of p53 and BAX and downregulation of Bcl-xL (Figure 2). In the human tongue squamous-cell carcinoma cell line SCC-4, baicalein shifts this apoptotic balance by upregulating the expression of p53, BAX, Cyto-C, and caspase-3/9 while suppressing the expression of BCL-2, thereby triggering apoptosis through a Ca²⁺-linked mitochondrial pathway. ²⁴ In BGC-823 and SGC-803 human gastric cancer cell lines, baicalin promotes apoptosis by regulating BCL-2/BAX expression and activating caspase-3 and caspase-9. ²⁵ In HepG2 cells, baicalein induces apoptosis by disrupting mitochondrial function and shifting the balance between pro- and anti-apoptotic BCL-2 family proteins. ²⁶ In HCT116 human colorectal cancer cells, baicalein exhibits a strong proapoptotic effect by activating caspase-3 and caspase-9. ²⁷ It also induces apoptosis in human colorectal adenocarcinoma cells (HT-29) by activating protein kinase B (AKT) in a p53-dependent manner. ²⁸

Figure 2.

Mechanisms of tumor cell apoptosis induced by baicalein and baicalin. These compounds can induce apoptosis via intrinsic and extrinsic pathways; they activate the first apoptosis signal (Fas) receptor and caspases-2, −3, −8, and −9, upregulate p53 and BAX, and downregulate Bcl-xL. They can also activate the DNA damage response pathway, poly(ADP-ribose) polymerase (PARP), reactive oxygen species (ROS)-mediated AMPK signaling, ROS-induced mitochondrial dysfunction, and endoplasmic reticulum (ER) stress.

Activation of the DNA Damage Response Pathway

The DNA damage response, a component of the mitochondrial apoptotic pathway, triggers the activation of the caspase cascade in response to RNA or DNA damage (Figure 2). In HCT116 colorectal cancer cells, baicalein elicits apoptosis by upregulating the expression of growth arrest and DNA damage-inducible alpha and activating both c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) in a reinforcing loop. ²⁹ In CRC cells, baicalein promotes apoptosis by downregulating the expression of circular RNA myosin heavy chain 9 and hepatoma-derived growth factor while upregulating that of miR-761. ³⁰ It can also induce apoptosis in CRC cells by suppressing oncogenic microRNAs. ³¹

Poly (ADP-Ribose) Polymerase (PARP) Activation

Excessive PAR stimulation disrupts mitochondrial function, leading to the release of Cyto-C and the initiation of a caspase-driven apoptotic cascade (Figure 2). Notably, baicalein induces HCT116 cell apoptosis by promoting PARP cleavage and inducing morphological changes. ³²

Reactive Oxygen Species (ROS)-Mediated AMPK Pathway

As signaling molecules, ROS trigger AMP-activated protein kinase (AMPK), inhibiting both cell proliferation and tumor initiation (Figure 2). Using water-soluble tetrazolium-1 assays, F-actin staining, flow cytometry, immunofluorescence, and western blotting, Choi et al demonstrated that S. baicalensis preferentially induces apoptosis in human tongue squamous-cell carcinoma via mitochondrial and MAPK pathways. ³³ Jia et al indicated that baicalin triggers apoptosis in cholangiocarcinoma cells via the AMPK–mammalian target of rapamycin complex 1 (mTORC1)–70 kDa ribosomal protein S6 kinase (p70S6K) axis. ³⁴

ROS-Induced Mitochondrial Dysfunction

Elevated ROS levels can induce mitochondrial dysfunction (Figure 2). In SW620 CRC cells, baicalin activates caspases-3, −8, and −9 by inducing ROS production, ultimately leading to apoptosis. ³⁵ Moreover, it upregulates the expression of the DNA-binding E3 ubiquitin-protein ligase DEPP, which acts as an antioxidant, and activates downstream Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and p16/Retinoblastoma protein pathways, driving CRC cells into senescence. ³⁶

ER Stress

Disruption of ER homeostasis contributes to apoptosis (Figure 2). Kuo et al reported that baicalin induces apoptosis in human J5 liver cancer cells primarily through ER-dependent G2/M arrest, mitochondrial caspase activation, and the apoptosis-inducing factor and endonuclease G pathways. ³⁷

Apoptosis via Other Signaling Pathways

In EsCC-109 esophageal squamous carcinoma cells, baicalein promotes apoptosis by modulating the PI3K/AKT axis. ³⁸ In HCC cells, baicalin reduces cell viability, induces cell cycle arrest, and triggers apoptosis by repressing histone deacetylase 10 via miR-3178. ³⁹ In gallbladder cancer, it induces mitochondrial apoptosis by inhibiting nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB), upregulating BAX, downregulating Bcl-2, and activating caspase-3/9. Notably, these molecular effects translate into significant tumor suppression in vivo. ⁴⁰ In hepatocellular carcinoma cells, baicalin induces apoptosis by modulating the RelB/p52 complex, signal transducer and activator of transcription 3 (STAT3) signaling, and IFN-γ levels, ultimately attenuating tumor growth. ⁴¹

Autophagy-Mediated Cell Death in Digestive System Tumors

Autophagy is a cellular process that involves the degradation of damaged, redundant, nonessential, or abnormal components through lysosome-mediated vacuolar sequestration. ⁴² It fundamentally governs tumor evolution and influences the effectiveness of anticancer treatments. ⁴³ In HepG2 cells, baicalein treatment induces a dose- and time-dependent decline in phosphorylated AKT (Ser473), ULK1 (Ser757), and 4EBP1(Thr37 and Ser65) expression levels, a pattern consistent with the suppression of the AKT/mTOR cascade and consequent autophagy activation. ⁴⁴ Wang et al reported that baicalein triggers ER stress in liver cancer cells, shifting the balance toward apoptosis while downregulating autophagy. ⁴⁵

Collectively, these findings indicate that baicalein and baicalin can induce tumor cell death via multiple apoptotic pathways and autophagy, underscoring their therapeutic potential in digestive system malignancies.

Cell Cycle Arrest, Growth, and Proliferation

The cell cycle progresses through four phases: G1, S, G2, and M. Arresting cells at G1 or S inhibits DNA replication, while halting progression in G2 or M prevents mitosis. ⁴⁶ Moreover, cell cycle advance is tightly regulated by four essential components: cyclin-dependent kinases (CDK), their cyclin cofactors, CDK inhibitors, and the phosphorylated form of retinoblastoma protein (Rb). ⁴⁷

Scutellaria baicalensis modulates digestive tumor cell growth at multiple stages of the cell cycle (Figure 3), inducing cell cycle arrest at the G0/G1, S, and G2/M phases. In terms of the G0/G1 phase arrest, baicalein effectively arrests CRC cells in the G1 phase, inhibits transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT), suppresses cell proliferation, migration, and invasion, and promotes p53-independent apoptosis. ⁴⁸ In oral-cancer cells, baicalein induces G1 phase arrest by promoting cyclin D1 degradation, activating aryl-hydrocarbon receptors, and maintaining Rb in its hypophosphorylated, growth-suppressive state. ⁴⁹ Zheng et al revealed that baicalein blocks the β-catenin pathway, curtailing cyclin D1 transcription and trapping cells in G0/G1 while suppressing proliferation. ⁵⁰ In terms of S-phase arrest, baicalein activates caspases 3 and 9, induces S-phase arrest, and promotes apoptosis in HCT116 cells. ⁵¹ Similarly, baicalein induces and sustains S-phase arrest in SGC-7901 gastric cancer cells. ⁵² In pancreatic cancer cells, high concentrations of baicalin inhibit cell cycle progression in the S phase. ⁵³ In terms of G2/M phase arrest, S. baicalensis halts HepG2 cell growth by inducing a G2/M blockade. ⁵⁴ Baicalin and baicalein significantly increase the proportion of HepG2 cells arrested in the G2/M phase and induce sub-G1 peak accumulation in Hep3B cells, indicating cell cycle arrest and apoptosis. ⁵⁵ Moreover, baicalein alters the miRNA expression profile in Bel-7402 cells, upregulates p21/CDKN1A and P27/CDKN1B, inhibits the PI3K/AKT pathway, and induces S and G2/M phase arrest, thereby suppressing proliferation in both Bel-7402 and Hep3B cells. ⁵⁶

Figure 3.

Inhibition of tumor cell proliferation and cell cycle arrest of baicalein and baicalin.

Cell growth depends on the coordinated progression of DNA replication and cytokinesis, tightly regulated by the cell cycle. ⁵⁷ Therefore, arresting the cell cycle can effectively inhibit tumor proliferation and growth, making cell cycle control a critical strategy in cancer treatment. Notably, baicalin and baicalein exhibit significant regulatory effects on the proliferation of digestive system tumor cells through various molecular pathways. For example, baicalein suppresses HCT116 cell growth by arresting the cell cycle, decreasing ezrin expression levels, and promoting p53-related signaling. ⁵⁸ Moreover, baicalin inhibits the proliferation of hepatocellular carcinoma cells while driving apoptosis and cycle arrest by modulating the miR-3178/HDAC10 pathway. ⁵⁹ In vitro, baicalin inhibits cell proliferation, triggers apoptosis, and causes cell cycle arrest; in vivo, it suppresses tumor growth and improves survival. ⁶⁰ Using pathway array technology, Ye et al demonstrated that S. baicalensis exerts a potent antiproliferative effect on HepG2 cells by inducing G2/M phase arrest and modulating the hepatocellular carcinoma signaling network. ⁶¹ In hepatic cancer cells, baicalein suppresses growth and survival by downregulating the expression of CD24. ⁶² In hepatocellular carcinoma, baicalein preferentially inhibits growth by suppressing the MEK-ERK signaling cascade and the intrinsic apoptotic pathways. ⁶³

Overall, baicalin and baicalein inhibit the proliferation of digestive system tumor cells through various molecular pathways, such as by promoting cell death through apoptotic and autophagic pathways and inducing cycle arrest at different phases of the cell cycle.

Inhibition of Tumor Cell Invasion and Migration

Tumor cell invasion and metastasis are critical drivers of cancer progression, with metastasis accounting for the majority of cancer-related mortality.^64,65 Invasion can occur through both individual and collective cellular migration, the latter being a hallmark of many metastatic tumors. ⁶⁶ Therefore, targeting tumor cell invasion and metastasis represent an effective therapeutic strategy. Baicalin can inhibit metastasis by suppressing the Wnt/β-catenin and TGF-β//EMT signaling pathways. It further impedes angiogenesis by suppressing the expression of vascular endothelial growth factor (Figure 4). These antimetastatic and antiangiogenic effects have been particularly noted in gastrointestinal tumors. For example, baicalein inhibits gastric cancer cell migration by blocking the p38 pathway. ⁶⁷ It also suppresses the migration and invasion of gastric adenocarcinoma cells by downregulating the TGF-β/Smad4 axis. ⁶⁸ In colorectal carcinoma, baicalein impedes tumor invasiveness by inhibiting ERK signal transduction. ⁶⁹ It also inhibits colorectal cancer growth, dissemination, and metastasis by modulating the p53/p21 axis and suppressing Snail-mediated EMT. ⁷⁰ In vivo, baicalin can partially suppress xenograft tumor growth by downregulating circMYH9 and hepatoma-derived growth factor and upregulating miR-761. ⁷¹ In CRC, baicalein inhibits cell migration and invasion by suppressing matrix metalloproteinase (MMP)-2 and MMP-9 through AKT pathway inhibition. ⁷² Furthermore, baicalin suppresses HCC growth and metastasis by blocking rho-associated protein kinase 1 (ROCK1)-mediated glycogen synthase kinase (GSK)-3β/β-catenin signaling. ⁷³ Similarly, in vivo administration of baicalein significantly reduces the adhesion, migration, invasion, and proliferation of human HCC cells. ⁷⁴ Chen et al corroborated that baicalein impedes HCC dissemination by attenuating the ERK signaling pathway. ⁷⁵ Notably, when combined with gemcitabine and docetaxel, low-dose baicalein markedly inhibits pancreatic cancer cell migration. ⁷⁶ Baicalein also suppresses pancreatic cancer cell growth and invasiveness by inhibiting NED9 and its downstream AKT/ERK cascade. ⁷⁷

Figure 4.

Inhibition of tumor metastasis and angiogenesis of baicalein and baicalin.

Reversal of Drug Resistance

Multidrug resistance (MDR) poses a major challenge in cancer treatment. MDR refers to the reduced efficacy of chemotherapy due to tumor cell insensitivity to multiple anticancer drugs and can be classified as endogenous (pre-existing) or acquired (developed post-treatment). ⁷⁸ In this context, baicalin and baicalein have demonstrated distinct therapeutic potential in overcoming MD.For example, Chen et al demonstrated that baicalein resensitizes hypoxic AGS gastric cancer cells to 5-fluorouracil by inhibiting glycolysis and disrupting the phosphatase and tensin homolog–AKT–hypoxia-inducible factor-1 α axis. ⁷⁹ Li et al demonstrated that baicalein restores chemosensitivity in the MDR hepatoma line Bel7402/5-Fluorouracil, which is normally refractory to 5-fluorouracil and epirubicin. ⁸⁰ Notably, baicalin and baicalein also enhance chemotherapeutic efficacy when used in combination. At low concentrations, baicalin synergistically enhances nsPEF-induced cytotoxicity and necrosis in HCC cells while protecting normal hepatocytes. ⁸¹

In summary, these findings underscore the therapeutic potential of baicalin and baicalein for gastrointestinal malignancies, especially in overcoming chemoresistance.

Tumor Prevention

Prevention is a critical component of cancer management. Baicalin has demonstrated preventive effects against gastrointestinal tumors. Using network pharmacology and bioinformatics, Ma et al investigated the mechanisms of baicalin in HCC, identifying CDK1 and tumor protein 53 as key targets. Specifically, baicalin downregulates heat shock protein 70 expression, contributing to its chemopreventive activity. ⁸² Moreover, Park et al reported that baicalin upregulates reduced NAD(P)H:quinone oxidoreductase 1 in Hepa 1c1c7 cells by transactivating both activator protein 1 and NF-κ-B, supporting its potential as a chemopreventive agent through the induction of phase II detoxification enzymes. ⁸³

Discussion

Gastrointestinal system tumors represent a growing global health burden, owing to their high incidence and mortality rates. Available treatments exhibit limited efficacy, underscoring the urgent need for improved therapeutic strategies. Owing to their low toxicity and high therapeutic activity, herbal medicines are increasingly employed in cancer treatment. ⁸⁴ In vivo and in vitro experiments have demonstrated that S. baicalensis exhibits potential antitumor effects, attributed to its flavonoids baicalein and baicalin. Both baicalein and baicalin possess anti-inflammatory and antioxidant activities, inhibit angiogenesis, induce tumor cell cycle arrest, and enhance the tumor microenvironment. These effects are achieved by inhibiting cancer cell proliferation and inducing apoptosis. Baicalein and baicalin also suppress tumor growth by modulating key cellular signaling pathways, such as MAPK, NF-κB, and PI3K/AKT. Baicalein can directly disrupt DNA synthesis and repair in cancer cells, acting as a direct active agent. In contrast, baicalin exerts its effects through its metabolic products, requiring its conversion into baicalein within the body to achieve its anticancer activity.^85,86 The present review explores the pharmacological mechanisms of baicalein and baicalin in the treatment of digestive system tumors. These include promoting apoptosis and autophagy, inducing tumor cell cycle arrest, inhibiting growth and proliferation, suppressing tumor cell invasion and migration, reversing drug resistance, and preventing tumor development.

Baicalein and baicalin induce apoptosis through the following pathways: (1) intrinsic or extrinsic pathways by activating Fas, caspases-2, −3, −8, −9, upregulating p53 expression, downregulating BCL-xL, and upregulating Bax; (2) DNA damage response pathway, in which DNA or RNA damage leads to apoptosis by activating the caspase cascade; (3) excessive PARP activation, which results in mitochondrial dysfunction and the release of apoptosis-inducing factors such as Cyto-C, which in turn activate caspases and trigger the apoptotic cascade; (4) ROS-mediated activation of the AMPK pathways, which in turn inhibit cell proliferation and tumorigenesis; (5) enhancing ROS-induced mitochondrial dysfunction in various cancer cells; (6) disrupting ER homeostasis; and (7) certain signaling pathways that induce apoptosis, such as the PI3K/AKT, miR-3178/HDAC10, NF-κB, RelB/p52, and PI3K/AKT/mTOR pathways. In addition, baicalein and baicalin inhibit the invasion and metastasis of digestive system tumors, reverse drug resistance, and prevent tumorigenesis through various signaling molecules and pathways. These pathways include the p38, TGF-β/Smad4, ERK, AKT, and ROCK1/GSK-3β/β-catenin signaling pathways.

As natural plant compounds, baicalein and baicalin offer higher safety and fewer side effects than synthetic drugs.^87–89 These compounds can synergistically enhance treatment efficacy by targeting tumors through multiple biological pathways. For example, both baicalein and baicalin can augment the effects of certain chemotherapy drugs, such as cisplatin. However, baicalein possesses relatively low lipid solubility and limited bioavailability, requiring the use of additional carriers during administration. Moreover, when combined with other drugs, baicalein may affect drug metabolism and efficacy, suggesting potential for adverse reactions. Although laboratory studies have demonstrated promising activity, clinical data on baicalein and baicalin are currently limited, highlighting the need for further research to evaluate their safety and efficacy. Furthermore, while this present review aimed to systematically integrate and synthesize available findings to present a comprehensive overview of the pharmacological actions of baicalin, current research predominantly addresses its effects on isolated tumor sites or discrete mechanisms, with limited studies on its preventive effects. This likely reflects the multifactorial etiology, prolonged latency, and heterogeneity of disease progression of gastrointestinal tumors, which complicate mechanistic understanding and limit opportunities for effective prevention.

The novelty of this review lies in its systematic and detailed synthesis of the pharmacological mechanisms of baicalin and baicalein, providing insights that may inform the development of more comprehensive and evidence-based strategies for preventing and treating gastrointestinal cancer. However, this review has some limitations. It did not encompass all pharmacologically active components of S. baicalensis and relied solely on English-language sources, which may introduce bias. Moreover, the scarcity of clinical trial data limits both the depth of discussion and the interpretation of specific findings. Future investigations should address understudied areas, incorporating large-scale clinical validation. Enhanced international collaboration and shared research resources will be essential for strengthening the evidence base and advancing effective treatment strategies for gastrointestinal malignancies.