Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway

Abstract

Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype and accounts for more than 15% of all lung cancer cases. Cisplatin [cis-diamminedichloroplatinum (CDDP)]-based combination chemotherapy is the cornerstone for all stages of SCLC. However, acquired multidrug resistance (MDR) and intolerable toxicities lead to a high mortality rate in SCLC patients. Gallic acid [3,4,5-trihydroxybenzoic acid (GA)] is a natural botanic phenolic compound which can induce cell apoptosis in several types of cancers. In the present study, we aimed to explore the anticancer effects of GA on human SCLC H446 cells and its promotive effects on the anticancer activities of cisplatin. The viability of the H446 cells was analyzed by MTT assay. Morphological changes in the H446 cells were observed under an inverted microscope. Apoptosis induction was determined by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. The level of reactive oxygen species (ROS) was assessed by 2'7'-dichlorofluorescein diacetate (DCFH‑DA), mitochondrial membrane potential (MMP) by JC-1, and western blotting was used to examine the expression of mitochondrial apoptosis-related proteins. The results showed that both GA and cisplatin changed the morphology, inhibited the growth and induced apoptosis in the H446 cells by inducing generation of ROS, disruption of MMP, downregulation of XIAP expression, and upregulation of Bax, Apaf-1, DIABLO and p53 expression. More importantly, GA combined with cisplatin exhibited synergistic effects on inducing of these pro-apoptotic mediators and modulating the activation of apoptosis-related molecules. However, inhibition of the generation of ROS by N-acetyl-l-cysteine (NAC), a specific ROS inhibitor, reversed the cell apoptosis induced by cisplatin combined with GA. In conclusion, the results from the present study revealed that GA exhibited an anticancer effect on human SCLC H446 cells and enhanced the antitumor activities of cisplatin via the ROS-dependent mitochondrial apoptotic pathway.

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non‑small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway

“…With advances in research on Traditional Chinese Medicine (TCM), many agents extracted from natural plants have attracted increasing levels of public attention in recent years for their apparent favorable pharmacokinetic characteristics and mild side-effects. Gallic acid (3,4,5-trihydroxybenzoic acid; GA), a natural phenolic compound, is one such plant extract that is present in abundance in tea, grapes, gall-nuts and red wine (6,7). It has been reported to possess various pharmacological and biological properties, including antibacterial, antiviral and antitumor activities.…”

Castanea sativa Mill. bark extract exhibits chemopreventive properties triggering extrinsic apoptotic pathway in Jurkat cells

“…Ellagic and gallic acids as well as tannins have been demonstrated to induce apoptosis in different in vivo and in vitro models [24–28]. …”

Evaluation of In Vitro Antioxidant and Anticancer Properties of the Aqueous Extract from the Stem Bark of Stryphnodendron adstringens

“…Among the compounds identified, gallic acid shows cytotoxic effects against various tumor cell lines, including basal-like breast [81], non-small cell lung [82], oral squamous cell carcinoma [83] and hepatocellular cancer cell lines, showing no cytotoxic effects on normal cells [84]. In murine B16F10 melanoma cells, this compound is described for inducing apoptosis through the mitochondrial pathways by promoting the overexpression of the enzymes caspase-3, caspase-9 and PARP-1 as well as the pro-apoptotic proteins Bax and Bad; it also promotes the under-expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL [85].…”