Potential Antitumor Effects of 6-Gingerol in p53-Dependent Mitochondrial Apoptosis and Inhibition of Tumor Sphere Formation in Breast Cancer Cells

Abstract

Hormone-specific anticancer drugs for breast cancer treatment can cause serious side effects. Thus, treatment with natural compounds has been considered a better approach as this minimizes side effects and has multiple targets. 6-Gingerol is an active polyphenol in ginger with various modalities, including anticancer activity, although its mechanism of action remains unknown. Increases in the level of reactive oxygen species (ROS) can lead to DNA damage and the induction of DNA damage response (DDR) mechanism, leading to cell cycle arrest apoptosis and tumorsphere suppression. Epidermal growth factor receptor (EGFR) promotes tumor growth by stimulating signaling of downstream targets that in turn activates tumor protein 53 (p53) to promote apoptosis. Here we assessed the effect of 6-gingerol treatment on MDA-MB-231 and MCF-7 breast cancer cell lines. 6-Gingerol induced cellular and mitochondrial ROS that elevated DDR through ataxia-telangiectasia mutated and p53 activation. 6-Gingerol also induced G0/G1 cell cycle arrest and mitochondrial apoptosis by mediating the BAX/BCL-2 ratio and release of cytochrome c. It also exhibited a suppression ability of tumorsphere formation in breast cancer cells. EGFR/Src/STAT3 signaling was also determined to be responsible for p53 activation and that 6-gingerol induced p53-dependent intrinsic apoptosis in breast cancer cells. Therefore, 6-gingerol may be used as a candidate drug against hormone-dependent breast cancer cells.

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“…Its upregulation leads to induction of cell cycle arrest and apoptosis [ 66 , 67 ]. Although MDA MB-231 cells carry a mutated p53 gene (R280K mutation), mechanistic studies demonstrated that treatment with anticancer agents inducing p53-dependent intrinsic apoptosis (6-gingerol) resulted in p53 expression and quick apoptosis execution, supporting the hypothesis that p53 in MDA MB-231 is indeed a gain-of-function mutant [ 68 , 69 , 70 ]. Similarly, the expression of apoptosis regulatory genes evaluated by PCR following treatment of Caco-2 cells with some apoptotic inducers ( Drimia calcarata bulb extracts) revealed p53 upregulation, even though p53 was not detected in the untreated cells [ 71 ].…”

Pivotal Role of Iron Homeostasis in the Induction of Mitochondrial Apoptosis by 6-Gingerol Through PTEN Regulated PD-L1 Expression in Embryonic Cancer Cells

“…A natural compound that can induce DDR, thereby inducing cell cycle arrest and apoptosis in cancer cells, should be considered as a candidate for further studies. Previous studies showed that 6-gingerol can induce cell cycle arrest and apoptosis against several cancer types (28,34,38). The anti-cancer activity of a natural compound also depends on its capability to induce ROS generation (39).…”

“…It exhibits antioxidant, anti-platelet, anti-inflammatory, anti-proliferative, and anti-cancer activities (30)(31)(32)(33). 6-Gingerol has been reported to induce anti-tumor activity against breast (28), colorectal (34), gastric (35), and pancreatic cancers (36). However, the mechanism of cell death by 6-gingerol in CSCs is unknown.…”

“…Patients suffering from cancer also struggle with the adverse effects of chemotherapeutic drugs ( 25 , 26 ). Cancer treatments that use natural compounds are good alternatives, due to the possibility of a multi-targeted treatment with fewer side effects compared to chemotherapeutics ( 27 , 28 ). Ginger is a very popular spice commonly used in Asian countries, and 6-gingerol is a bioactive phenolic compound and primary pharmacological component of ginger ( 29 ).…”

Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells

“…Even though targeting EGFR with tyrosine kinase inhibitor is a good approach against NSCLC, few of them were ineffective regarding tumor response, including Gefitinib [ 28 ]. Elevated levels of EGFR enable signal transduction in the cell cytoplasm, thereby promoting tumorigenesis by contributing to the transformation of cellular phenotypes for cancer cell proliferation and survival [ 29 ]. Generally, blocking of EGFR signals toward its downstream targets by chemotherapeutic drugs determines the tumor fate.…”