Thesis (M.Sc. in Pharm.)--Chulalongkorn University, 2013

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.