Oxaliplatin (Ox), a Pt(II) drug, is used to treat colorectal cancer (CRC), despite serious side effects and resistance [1]. Its main action is DNA adduct formation, but Ox also induces oxidative stress contributing to cancer cell death. Resistant cells often exhibit imbalance of key regulators of intracellular redox state, such as glutathion (GSH) and metallothionein (MTT), which can reduce cellular Pt accumulation due to a high affinity towards Pt [2, 3, 4]. Indeed, studies have described sulfur-rich Pt complexes in endolysosomal compartments [5, 6, 7] and increased Pt efflux through extracellular vesicles (EV) release in Pt-resistant cells [2].This leads to the hypothesis that Pt complexation and EV release may constitute a detoxification mechanism for resistant cells, but it also raises the question of whether, at the tissue level, EVs can propagate these metal complexes from one cell to another, with effects on recipient cells different from those induced by the original drug [8]. In this context, we aim to study the intracellular fate, quantification, biological activity and excretion of Ox in EV, thus helping to decipher the mechanisms of action and resistance of this drug.
In this project, we explored Pt internalization in different colorectal cancer cell lines and their generated EVs. We investigated intercellular Pt transfer and its impact on recipient cells, and compared the effects with the results obtained on cells directly exposed to Ox. Our first results showed a correlation between CRC Ox sensitivity and Pt internalization in cells and EVs, and a higher EV’s excretion for less sensitive cells. Interestingly, we also noticed an increased EV production from cells exposed to Ox compared to control cells. These results tend to support the hypothesis that EVs represent a mechanism of detoxification for cells exposed to Ox.