Platinum-based chemotherapeutic drugs as effective sensitizers of colon and prostate cancer cells to the apoptotic action of TRAIL

Platinum-based chemotherapeutic drugs such as cisplatin or oxaliplatin are used in therapy of various solid tumors, but their application is limited due to acquired/inherited cancer cell resistance and serious side effects to normal tissues. A novel platinum (IV) adamantylamine ligand-containing complex LA-12 has been introduced and shown as highly effective in elimination of several cancer cell types including those resistant to cisplatin. Our previous and current work highlighted the abilities of LA-12 to trigger colon cancer cell death (apoptosis) in significantly lower doses compared to cisplatin or oxaliplatin, and independently on the cell confluency or p53 status. In addition, we were the first to demonstrate that compared to cisplatin, LA-12 can act as a more effective sensitizer of colon and prostate cancer cells to apoptosis induced by TRAIL (tumor necrosis factor-related apotosis inducing ligand), a unique cytokine with promissing anticancer potential.

We examined and compared the molecular mechanisms of the individual action of the conventionally used and novel platinum-based drugs as well as their ability to substantially contribute to the enhancement of TRAIL-induced apoptosis in several human colon and prostate cancer cell lines. The stimulation of apoptotic response following the LA- 12/cisplatin + TRAIL combination was demonstrated at the level of TRAIL death receptors and/or mitochondria. The results of our detailed molecular investigations, especially focused on the mechanisms of caspase activation and the role of selected Bcl-2 family proteins will be presented in our contribution, and the potential therapeutic targets and the relevance of the drug application in cancer treatment will be discussed.

This work was supported by the IGA of the Ministry of Health of the Czech Republic (NT 11201-5) and Czech Science Foundation No. P301/11/1730.