EFFECT OF LONG-TERM NITRIC OXIDE EXPOSURE ON CHEMOTHERAPEUTIC RESISTANCE IN H292 LUNG CARCINOMA CELLS

Abstract

The effect of extended exposure of cancer cells to nitric oxide (NO), an endogenous mediator frequently found to be increased in a tumor area, is largely unknown. This study aimed to investigate the effect of NO treatment for 7-14 days on the susceptibility of lung cancer cells to chemotherapeutic agents, namely, cisplatin, doxorubicin, and etoposide. We report herein that long-term NO exposure for 7-14 days rendered the lung cancer cells resistant to chemotherapeutic agents, namely, cisplatin, doxorubicin, and etoposide, in dose- and time-dependent manners. The underlying mechanism was found to involve the adaptive responses of the cells, by increasing survival due to increase in the level of caveolin-1 (Cav-1) and anti-apoptotic Bcl-2, and up-regulation of activated Akt. The gene manipulation study revealed that the increase of activated Akt and Bcl-2 was responsible for the resistance to all tested drugs (cisplatin, doxorubicin, and etoposide), while the up-regulation of Cav-1 only attenuated cell death mediated by doxorubicin and etoposide. Interestingly, NO-mediated drug resistance was found to be reversible when the cells were further cultured in the absence of NO for 5 days. These findings reveal the novel role of NO presenting in the tumor environment in attenuating chemotherapeutic susceptibility and may be beneficial in contriving strategies to treat the disease.