p53 is the most frequently mutated tumor-suppressor gene in human cancers. Unlike other tumor-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the expression of full-length mutant p53 protein. Mutant p53 proteins not only lose their tumor-suppressor function, but may also gain new oncogenic functions and promote tumorigenesis. Here, we showed that silencing of endogenous p53-R273H contact mutant, but not p53-R175H conformational mutant, reduced AKT phosphorylation, induced BCL2-modifying factor (BMF) expression, sensitized BIM dissociation from BCL-XL and induced mitochondria-dependent apoptosis in cancer cells. Importantly, cancer cells harboring endogenous p53-R273H mutant were also found to be inherently resistant to anoikis and lack BMF induction following culture in suspension. Underlying these activities is the ability of p53-R273H mutant to suppress BMF expression that is dependent on constitutively active PI3K/AKT signaling. Collectively, these findings suggest that p53-R273H can specifically drive AKT signaling and suppress BMF expression, resulting in enhanced cell survivability and anoikis resistance. These findings open the possibility that blocking of PI3K/AKT will have therapeutic benefit in mutant p53-R273H expressing cancers.

Cancer cells meet their energy need by predominantly increased uptake of glucose, high rate of glycolysis, and increased production of lactate even in the presence of adequate oxygen.  This process was proposed by Otto Warburg and named after him as the Warburg effect. The development of drugs that target glucose intake and aerobic glycolysis or lactic acid secretion of cancer cells is a newer approach for drug discovery. We have tested five purified plants‐derived compounds such as curcumin, quercetin, ellagic acid, resveratrol, and indole‐3‐carbinol in HeLa cells for cytotoxicity, inhibition of metastasis, and modulation of lactate–pyruvate metabolism. Standard biochemical methods were used for glucose, lactic acid, and pyruvic acid measurement. The cell viability was determined by MTT assay. Cell migration was checked by wound healing assay. A dose‐dependent cytotoxic effect and inhibition of cell migration were observed in all the tested compounds. A decrease in the lactate and increase in pyruvate level was observed in all the tested compounds except ellagic acid. Our finding suggests that tested phytocompounds are associated with the metabolic reprogramming of cancer cells and execute the cytotoxic effect. These compounds could be used for cancer prevention and therapy.

Cervical cancer is a major human papillomavirus-related disease and is the fourth leading cause of death by cancer among women. Plants are an important source of anticancer compounds and many of them are currently used in the treatment of cancer. Several reports suggest the efficacy of plant-derived compounds increases when used in combination. This study was carried out to evaluate the effect of four plant-derived compounds such as curcumin (C), ellagic acid (E), quercetin (Q), and resveratrol (R) when used alone or in combinations using HeLa cervical cancer cells. All four phytocompounds showed effective cytotoxic activities in targeting HeLa cervical cancer cells as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium assay. The selected phytocompound combinations C + E, C + Q, and Q + R work synergistically while the combination C + R shows additive effects. All four phytocompounds reduce cell migration as determined by in vitro woundhealing assay. The expression level of the epidermal growth factor receptor is significantly downregulated both in individual and combination. The flow cytometry analysis of cell cycle indicates that individual drugs curcumin, ellagic acid, quercetin, and resveratrol, each with 20 µM effectively arrested cell cycle at the S-phase while the combination of drugs (10 + 10 µM) at the G2/M phase.

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