Autophagy Inhibition Promotes 5-Fluorouraci-Induced Apoptosis by Stimulating ROS Formation in Human Non-Small Cell Lung Cancer A549 Cells

Abstract

Chemotherapy is an important option for the treatment of various cancers including lung cancer. However, tumor resistance towards cytotoxic chemotherapy has become more common. It has been reported that autophagy is one of the processes contributing to this resistance. In the present study, we found that the anti-cancer drug 5-fluorouraci(5-FU) could induce autophagy in A549 cells. 5-FU treatment could lead to the conversion of LC3 I/II, the up-regulation of Beclin-1, the down-regulation of p62 and the formation of acidic vesicular organelles (AVOs) in A549 cells. Pre-treatment of cancer cells with 3-MA or siAtg7 could enhance 5-FU-induced apoptosis through the activation of caspases, and the caspase inhibitor z-VAD-fmk rescued the cell viability reduction. Furthermore, the inhibition of autophagy also stimulated ROS formation and scavenging of ROS by antioxidant NAC inhibited caspase-3 activity, prevented the release of cyt-c from mitochondria and eventually rescued cancer cells from 5-FU-mediated apoptosis. These results suggest that 5-FU-elicited autophagic response plays a protective role against cell apoptosis and the inhibition of autophagy could sensitize them to 5-FU-induced caspase-dependent apoptosis through the stimulation of ROS formation.

PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells

“…Earlier studies also report that the inhibition of autophagosome and lysosome fusion by CQ promoted apoptosis. 43 In another way, suppression of autophagosome and lysosome fusion might subvert the capacity of cells to get rid of damaged organelles or misfolded proteins, which in turn would favor apoptosis. 43 Similarly, our in vitro studies indicated an interchanging circuit of survival and death stimulators, viz.…”

“…43 In another way, suppression of autophagosome and lysosome fusion might subvert the capacity of cells to get rid of damaged organelles or misfolded proteins, which in turn would favor apoptosis. 43 Similarly, our in vitro studies indicated an interchanging circuit of survival and death stimulators, viz. the BCL2 and PAWR mutual interaction in pursuing this switchover (due to 3-AWA treatment concentrations) for the sake of maintaining cellular homeostasis.…”

Potentiation of resveratrol-induced apoptosis by matrine in human hepatoma HepG2 cells

“…However, matrine alone weakly inhibits proliferation of cancer cell lines with an IC 50 value of 2-16 mM (17). Combination of anticancer agents for cancer therapy and prevention has been extensively studied in numerous in vivo and in vitro models (31,32). Since each agent may have its own targets and also share common targets, the combination of two anticancer agents may exert a synergistic effect.…”

Autophagy in the Pathogenesis of Pulmonary Disease

“…On the other hand, the amino acids supplied by autophagy are fundamental to the survival and proliferation of established cancer cells (2). In vitro experiments have demonstrated that autophagy inhibition is a potential strategy to overcome the mechanisms of drug resistance to cancer chemotherapy in human NSCLC (60), and several clinical trials using autophagy-inhibiting agents in combination with conventional cytotoxic agents are active and recruiting patients to assess novel modalities of lung cancer treatment. However, both the tumor-suppressive and -promoting sides of autophagy activation and the systemic influence of autophagy inhibition must be taken into account for clinical application.…”