Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy

Melanoma is the deadliest form of skin cancer, which is notoriously aggressive and chemo-resistant, and for which there is little effective treatment available if it goes undetected. Curcumin from the tumeric spice (Curcuma longa) has long been used in Southeast Asian medicine to alleviate ailments and cure an array of diseases and disorders. It possesses anti-inflammatory, anti-oxidant and most importantly anti-carcinogenic activity. There have been contradictory reports discussing the efficacy of curcumin-induced death on melanoma. In this report we show that curcumin does induce apoptosis in A375 and the relatively resistant G361 malignant human melanoma cell lines at higher doses. Tamoxifen is an estrogen receptor (ER) blocker that is used for ER positive breast cancer treatment. Recently, tamoxifen has been shown to directly target the mitochondria. Given that curcumin is a pro oxidant and tamoxifen can act on mitochondria, we ask whether the combinatorial treatment could result in synergistic induction of apoptosis in chemo-resistant melanoma. Our results show a corresponding increase in phosphatidyl serine flipping, mitochondria depolarization and reactive oxygen species (ROS) generation by the combined treatment at lower doses. Interestingly, there was significant induction of autophagy along with apoptosis following the combined treatment. Importantly, non-cancerous cells are unaffected by the combination of these non-toxic compounds. However, once exposed to low doses of this co treatment, melanoma cells still retain signals to commit suicide even after removal of the drugs. This combination provides a non-toxic option for combinatorial chemotherapy with great potential for future use.