Desensitization of metastatic melanoma cells to therapeutic treatment through repeated exposure to dacarbazine

Abstract

Aberrant anti-cancer drug efflux mediated by membrane protein ABC transporters (ABCB5 and ABCG2) is thought to characterize melanoma heterogeneous chemoresistant populations, presumed to have unlimited proliferative and self-renewal abilities. Therefore, this study primarily aimed to investigate whether continuous exposure of melanoma cells to dacarbazine (DTIC) chemotherapeutic drug enriches cultures with therapy resistant cells. Thereafter, we sought to determine whether combining the genotoxic activity of DTIC with the oxidative insults of hypericin activated photodynamic therapy (HYP-PDT) could synergized to kill heterogenous chemoresistant melanoma populations. This study revealed that DTIC resistant (UCT Mel-1DTICR2) melanoma cells were less sensitive to all therapies than parental melanoma cells (UCT Mel-1), yet combination therapy was the most efficient. At the exception of DTIC treatment, both HYP-PDT and the combination therapy were effective in significantly reducing the Hoechst non-effluxing dye melanoma main populations (MP) compared to their side population (SP) counterparts. Likewise, HYP-PDT and combination therapy significantly reduced self-renewal capacity, increased expression of ABCB5 and ABCG2 transporters and differentially induced cell cycle arrest and cell death (apoptosis or necrosis) depending on the melanoma MP cell type. Collectively, combination therapy could synergistically reduce melanoma proliferative and clonogenic potential. However, further research is needed to decipher the cellular mechanisms underlying this resistance which would enable combination therapy to reach therapeutic fruition.

Keywords: ABC transporters; Dacarbazine (DTIC); Hypericin (HYP); Main population (MP); Melanoma; Photodynamic therapy (PDT); Side population (SP).