Different accumulation of cisplatin, oxaliplatin and JM216 in sensitive and cisplatin-resistant human cervical tumour...

The significance of reduced drug accumulation in resistance to cisplatin was investigated by using cisplatin, oxaliplatin and JM216 (hydrophobicity rank: JM216>oxaliplatin>cisplatin) in human squamous cell carcinoma cell line A431 and its cisplatin-resistant counterpart A431/Pt. While cisplatin showed a resistance factor of 2.6, oxaliplatin and JM216 circumvented the resistance. Platinum accumulation after cisplatin exposure was lower (2.4-fold) in A431/Pt than in A431 cells, whereas a similar accumulation was found in the two cell lines when oxaliplatin or JM216 were used, thereby suggesting the capability of the latter drugs to bypass the accumulation defect. In the A431 cell line platinum accumulated to a similar extent after exposure to cisplatin, oxaliplatin or JM216, while in A431/Pt cells, Platinum accumulation depended on the hydrophobicity of the drug, and an increased hydrophobicity favours the uptake. No difference in efflux of cisplatin was found between the two cell lines. The values of platinum-DNA binding in A431 cells were similar for cisplatin and JM216 and higher than those of oxaliplatin. In A431/Pt cells: (i) Pt-DNA binding levels of JM216 remained as in sensitive ones; (ii) Pt-DNA levels of cisplatin and oxaliplatin were very similar and nearly two-fold lower than those of JM216. Such results, in this cell system characterized by a low level of cisplatin resistance, support a model whereby platinum uptake occurs by a mechanism of facilitated diffusion, perhaps involving a gated channel, which can be lost during the selection of the drug-resistant variant(s). The hydrophobicity of the drug can be the key to bypass resistance.