Escin enhanced the efficacy of sorafenib by autophagy‐mediated apoptosis in lung cancer cells

Abstract Combining anti‐cancer drugs has been exploited as promising treatment strategy to target lung cancer. Synergistic chemotherapies increase anti‐cancer effect and reduce effective drug doses and side effects. In this study, therapeutic potential of escin in combination with sorafenib has been explored. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2 5‐diphenyltetrazolium bromide assay was used to calculate IC 50 values. The synergy was evaluated using Chou–Talaly algorithm. Cellular reactive oxygen species, mitochondrial membrane potential, annexin V, and cell‐cycle studies were done by flow‐cytometer, and autophagy biomarkers expression were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role, diethylnitrosamine‐induced lung cancer model was used to check the synergy of sorafenib/escin. Escin significantly reduced the IC 50 of sorafenib in A549 and NCIH460 cells. The combination of sorafenib/escin produced a 2.95 and 5.45 dose reduction index for sorafenib in A549 and NCI‐H460 cells. The combination of over‐expressed p62 and LC3‐II reflects autophagy block‐mediated late apoptosis. This phenomenon was reconfirmed by ATG5 knockdown. This combination also selectively targeted G0/G1 phase of cancer cells. In in vivo study, the combination reduced tumour load and lower elevated serum biochemical parameters. The combination of sorafenib/escin synergistically inhibits autophagy to induce late apoptosis in lung cancer cells' G0/G1 phase.