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 IC50 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 IC50 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.