Arvanil, a synthetic capsaicin mimetic, synergizes with Irinotecan to trigger enhanced apoptosis in Cisplatin‐resistant Human Lung Cancer

Abstract

Cisplatin‐based combination therapy is the first line treatment for human lung cancer patients. Initially, cisplatin shows excellent therapeutic response inducing remission in about 80% of lung cancer patients; however, the tumor inevitably relapses (within a year) and this relapsed tumor is resistant to cisplatin. Patients with platinum‐resistant or refractory disease have very limited options, as the only standard chemotherapy with an FDA‐approved drug, irinotecan has an objective response rate of approximately 3% and little or no survival benefit. Therefore, agents which improve the therapeutic response (of human lung cancers) towards irinotecan may be useful for the treatment of cisplatin‐resistant human lung cancer. Our published data show that the nutritional compound capsaicin sensitized human lung cancer cells towards the pro‐apoptotic activity of camptothecin (an analog of irinotecan) in cell culture and athymic mouse models. The administration of capsaicin causes stomach cramps, gastrointestinal irritation, gut pain and vomiting in patients. Arvanil is a non‐pungent synthetic capsaicin‐analog which displays potent growth‐suppressive activity in human lung cancer. The present study aims to investigate the combinatorial apoptotic activity of arvanil and irinotecan in cisplatin‐resistant lung cancer. Caspase‐3 activity assays reveal that the combination of irinotecan and arvanil displayed greater apoptotic activity in H69‐CPR human cisplatin‐resistant SCLC cells than the drugs used alone. These experiments were repeated in a second cisplatin‐resistant lung cancer cell line PC9‐CDDP and similar results were obtained. Chou‐Talalay isobologram analysis showed the interaction between irinotecan and arvanil is synergistic in H69‐CPR and PC9‐CDDP cells. The combination of arvanil/irinotecan showed a greater anti‐tumor activity in H69‐CPR tumors xenografted on chicken chorioallantoic membrane (CAM) and in SCID mice. In summary, the results of our studies pave the way for novel combination therapies for the management and treatment of drug resistant lung cancers in patients.