Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer

Abstract

Low response rate and recurrence are common issues in lung cancer; thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from Withania somnifera, as a potential anti–lung cancer and anti–lung cancer stem-like cell (CSC) agent. First, we demonstrated that WA exhibited potent cytotoxicity in several lung cancer cells, as evidenced by low IC50 values. WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects. The increase in p62 indicated that WA may modulate the autophagy flux followed by apoptosis. In vivo research also demonstrated the anti-tumor effect of WA treatment. We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity, at least through downregulation of mTOR/STAT3 signaling. Furthermore, the combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability. In addition, WA can further enhance the cytotoxic effect of cisplatin in lung CSCs. Therefore, WA alone or in combination with standard chemotherapy is a potential treatment option for EGFR wild-type lung cancer and may decrease the occurrence of cisplatin resistance by inhibiting lung CSCs.

Low Concentration of Withaferin a Inhibits Oxidative Stress-Mediated Migration and Invasion in Oral Cancer Cells

“…Withaferin A (WFA), a triterpenoid derived from the root or leaf of the medicinal plant Withania somnifera, is reported to exhibit antiproliferative properties and can induce apoptosis in several types of cancers such as leukemia [5], cervical [6], pancreatic [7], breast [8], lung [9], colorectal [10], and oral [11,12] cancer cells. These anticarcinogenic effects for WFA were based on high cytotoxic concentrations.…”

“…These cytotoxic concentrations of WFA were reported to induce reactive oxygen species (ROS)-mediated apoptosis in oral [12] and colon [10] cancer cells. ROS may induce a number of reactions such as apoptosis [5][6][7][8][9][10][11][12], autophagy, and endoplasmic reticulum stress [13]; however, its effect on migration has rarely been reported.…”

Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma

“…Phytochemicals are naturally occurring plant-derived compounds that have been widely used to treat a variety of malignant tumors due to their availability, biological activity, and nontoxic effects [4]. Emerging evidence suggests that numerous phytochemicals can reverse the resistance of various malignancies to cisplatin while counteracting organ toxicity caused by cisplatin [5][6][7]. Thus, in many types of malignancies, phytochemicals are candidates for overcoming cisplatin resistance.…”

Overview of the anticancer activity of withaferin A, an active constituent of the Indian ginseng Withania somnifera

“…The study brings further information revealing the WA inhibitory effects on EMT induction in NSCLC cells and proves the therapeutic action of WA against metastasis in NSCLC. Using in silico screening method, Hsu et al (2019) detected WA as being efficient anti-lung cancer stem-like cell (CSC), as well as anti-lung cancer agent. The results of the study revealed the ability of WA to stop the development of lung CSCs, reduce side population cells and stop spheroidforming ability in lung cancer by downregulation of mTOR/ STAT3 signalling.…”