Gambogic acid potentiates gemcitabine induced anticancer activity in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer accounting up to 80-85% of all lung cancer (LC) cases. Gemcitabine (Gem), a pyrimidine nucleoside antimetabolite, is widely used chemotherapy offering several months survival benefit in patients with NSCLC. The emergence of Gem resistance is a main clinical concern in cancer treatment and thus a continuous demand for development of new therapeutic strategies to improve its antitumor activity. Hence, we report an adjuvant therapeutic regimen based on natural compound, gambogic acid (GA) which has been shown to enhanced Gem induced inhibition of cancer cell growth, arrest cell cycle, and induce apoptosis by enhanced accumulation of Gem. The in vitro cell viability, clonogenicity, invasion, and migration assays demonstrated a significant higher therapeutic effect of Gem when it was combined with GA in A549 and H1299 cells. A better access of internalization of drug molecules achieved in rhodamine 123 assay when GA was used as adjuvant treatment. Further, GA and Gem combination significantly reduced tubular formation of HUVEC cells indicates lowering angiogenesis potential. Microarray and Western blot studies confirm that GA + Gem co-treatment strategy promotes cancer cell death by downregulating anti-apoptotic proteins, chemoresistance-associated proteins, and upregulation of apoptosis proteins. More importantly, a significant higher therapeutic benefit was noticed for GA and Gem combination in A549 xenograft mice model. Together, these results offer a rationale to evaluate the clinical translational possibility of GA as adjuvant therapy to overcome Gem resistance. This combination regimen can be a new therapeutic concept to eradicate this devastating disease.