Study of oxaliplatin resistance mechanisms in colorectal cancer : involvement of NOX1/calpains pathway

authors

• Chocry Mathieu

keywords

• Colorectal Cancer
• Chemoresistance
• Calpain
• NADPH Oxidase
• Oxaliplatin

abstract

Colorectal cancer is a major cancer in terms of frequency and mortality. This is the second leading cause of cancer death, with 17,500 deaths in France in 2011. The treatment of advanced stages is based on different chemotherapeuties including oxaliplatin. However, the development of resistance leads to therapeutic failures explaining the low survival rate. It is therefore crucial to identify the mechanisms of resistance and the actors involved and to discover new therapeutic approaches. We first investigated the role played by calpains and NOX1 in the development of resistance to oxaliplatin, studying oxaliplatin-resistant colorectal tumor cells. This allowed us to identify a signaling pathway involved in resistance to this chemotherapy.Secondly, we have studied the reversion of this resistance to oxaliplatin. A screening of different chemotherapies revealed a reversal of the resistant / sensitive status in our selected cells In the first part, our data highlight novel Nox1 regulations which differ according to the sensitivity of the cells to oxaliplatin. Our results also show that p38 MAPK could be a therapeutic target for treating colorectal cancers resistant to oxaliplatin. In the second part, we have identified a new treatment to induce apoptosis in our resistant cells. Indeed, gemcitabine may be a solution to treat patients who do not respond to oxaliplatin-based protocols.

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