Inhibitory Effect and Mechanism of Ursolic Acid on Cisplatin‐Induced Resistance and Stemness in Human Lung Cancer A549 Cells

Abstract

The survival rate of lung cancer patients remains low largely due to chemotherapy resistance during treatment, and cancer stem cells (CSCs) may hold the key to targeting this resistance. Cisplatin is a chemotherapy drug commonly used in cancer treatment, yet the mechanisms of intrinsic cisplatin resistance have not yet been determined because lung CSCs are hard to identify. In this paper, we proposed a mechanism relating to the function of ursolic acid (UA), a new drug, in reversing the cisplatin resistance of lung cancer cells regulated by CSCs. Human lung cancer cell line A549 was selected as the model cell and treated to become a cisplatin-resistant lung cancer cell line (A549-CisR), which was less sensitive to cisplatin and showed an enhanced capability of tumor sphere formation. Furthermore, in the A549-CisR cell line expression, levels of pluripotent stem cell transcription factors Oct-4, Sox-2, and c-Myc were increased, and activation of the Jak2/Stat3 signaling pathway was promoted. When UA was applied to the cisplatin-resistant cells, levels of the pluripotent stem cell transcription factors were restrained by the inhibition of the Jak2/Stat3 signaling pathway, which reduced the enrichment of tumor stem cells, and in turn, reversed cisplatin resistance in lung cancer cells. Hence, as a potential antitumor drug, UA may be able to inhibit the enrichment of the lung CSC population by inhibiting the activation of the Jak2-Stat3 pathway and preventing the resistance of lung cancer cells to cisplatin.