Antitumor activity of paclitaxel is significantly enhanced by a novel proapoptotic agent in non-small cell lung cancer

Abstract

Background: Newer targeted agents are increasingly used in combination chemotherapy regimens with enhanced survival and improved toxicity profile. Taxols, such as paclitaxel, independently potentiate tumor destruction via apoptosis and are used as first line therapy in patients with advanced non-small cell lung cancer (NSCLC). Procaspase-3-activating compound-1 (PAC-1) is a novel proapoptotic agent that directly activates procaspase-3 (PC-3) to caspase-3, leading to apoptosis in human lung adenocarcinoma cells. Hence, we sought to evaluate the antitumor effects of paclitaxel in combination with PAC-1.

Methods: Human NSCLC cell lines (A-549 and H-322m) were incubated in the presence of PAC-1 and paclitaxel. Tumor cell viability was determined by a tetrazolium-based colorimetric assay (MTT assay). Western blot and flow cytometric analysis were performed to evaluate expression of PC-3 and the proportion of apoptotic cells, respectively. A xenograft murine model of NSCLC was used to study the in vivo antitumor effects of PAC-1.

Results: PAC-1 significantly reduced the inhibitory concentration 50% of paclitaxel from 35.3 to 0.33 nM in A-549 and 8.2 to 1.16 nM in H-322m cell lines. Similarly, the apoptotic activity significantly increased to 85.38% and 70.36% in A-549 and H322m, respectively. Significantly enhanced conversion of PC-3 to caspase-3 was observed with PAC-1 paclitaxel combination (P < 0.05). Mice treated with a drug combination demonstrated 60% reduced tumor growth rate compared with those of controls (P < 0.05).

Conclusions: PAC-1 significantly enhances the antitumor activity of paclitaxel against NSCLC. The activation of PC-3 and thus the apoptotic pathway is a potential strategy in the treatment of human lung cancer.

Keywords: Non–small cell lung cancer; Paclitaxel; Procaspase-3 activating compound-1.