Gallic acid potentiates the apoptotic effect of paclitaxel and carboplatin via overexpression of Bax and P53 on the MCF‐7 human breast cancer cell line

Abstract

Despite advances in treatment, breast cancer remains the widest spread disease among females with a high mortality rate. We investigated the potential effects of gallic acid (GA) as supportive therapy in the management of breast cancer. Anti‐cancer activity with GA alone or in combination with paclitaxel and/or carboplatin was assessed by MTT assay and flow cytometry using annexin V/propidium iodide. The mechanism underlying the antiproliferative effects was investigated by measuring the expression of the pro‐apoptotic marker (Bax), CASP‐3, anti‐apoptotic (Bcl‐2), and, tumor suppressor (p53) by real‐time polymerase chain reaction (RT‐PCR) and western blot analysis. Cell cycle analysis was performed for the MCF‐7 breast cancer cell line. GA, paclitaxel, and carboplatin alone or in combination arrested cell cycle progression at the G2/M phase and induced Pre‐G1 apoptosis. RT‐PCR showed that the triplet combination significantly raised P53, Bax, and CASP‐3 mRNA expression (20.1 ± 1.41, 16.6 ± 0.43, and 20.04 ± 1.61, respectively) in MCF‐7 cells when compared to single or combined treatment (p < .0001) while anti‐apoptotic Bcl‐2 mRNA levels were decreased in all treated groups compared to untreated cells. Western blot data of tested apoptotic factors were consistent with RT‐PCR results. For the first time, we show that a minimum non‐toxic concentration of GA increased the efficacy of paclitaxel‐ and carboplatin‐induced MCF‐7 apoptotic cell death.

Hypoxia-Induced Intracellular and Extracellular Heat Shock Protein gp96 Increases Paclitaxel-Resistance and Facilitates Immune Evasion in Breast Cancer

“…As previously described, gp96 decreased p53 stability to promote its degradation in liver cancer ( 47 ), and inhibition of gp96 by its inhibitor upregulated p53 expressions to suppress Hepatitis B (HBV) replication ( 49 ). In addition, depletion of p53 increases paclitaxel-resistance in BC ( 46 , 50 , 51 ), indicating that existence of p53 sustains paclitaxel-sensitivity in BC. Based on the above information, we further evidenced that gp96 degraded p53 proteins instead of its mRNA in BC, and the promoting effects of gp96 overexpression on paclitaxel-resistance were abrogated by upregulating p53, which were in consistent with the previous publications ( 46 , 50 , 51 ).…”

“…In addition, depletion of p53 increases paclitaxel-resistance in BC ( 46 , 50 , 51 ), indicating that existence of p53 sustains paclitaxel-sensitivity in BC. Based on the above information, we further evidenced that gp96 degraded p53 proteins instead of its mRNA in BC, and the promoting effects of gp96 overexpression on paclitaxel-resistance were abrogated by upregulating p53, which were in consistent with the previous publications ( 46 , 50 , 51 ).…”

Gallic Acid Induces S and G2 Phase Arrest and Apoptosis in Human Ovarian Cancer Cells In Vitro

“…GA is a natural polyphenol with antibacterial, antiviral, and antitumor properties. Its tumor suppressive properties has, thus far, been demonstrated in prostate cancer [ 11 ], breast cancer [ 20 ], bladder cancer [ 21 ], cervical cancer and lung cancer [ 9 ].…”

A Network Pharmacology Analysis of the Systems-Perspective Anticancer Mechanisms of the Herbal Drug FDY2004 for Breast Cancer

“…156,[168][169][170][171][172][173][174][175][176][177] Gallic acid has anticancer activities for the suppression of proliferation, survival, cell cycle progression, invasion and migration of BC cells, which are mediated through the oncogenic EGFR, focal adhesion, MAPK, ErbB, PI3K-Akt, NF-kB, p53, Fas/FasL, cell cycle regulatory, and mitochondrial pathways. [178][179][180][181][182][183] Kaempferol and quercetin possess diverse anticancer mechanisms, including the induction of apoptosis and the suppression of proliferation, migration, invasion, cell cycle progression, metastasis, angiogenesis, and cancer stemness in BC cells; these therapeutic effects are mediated via pharmacological modulation of diverse crucial BC-associated signaling processes. [184][185][186][187][188][189][190][191][192][193] In addition, these chemical compounds may sensitize BC cells to various anticancer drugs.…”