The effect of reversing drug resistance and exact mechanism of novel platinum(Ⅳ)hybrids based on GSTs inhibitors
Based on the octahedral modifiable structures and kinetic inertness,platinum(Ⅳ)complexes have become antitumor prodrug candidates to mitigate platinum(Ⅱ)drug resistance and side effects.The nitrobenzoxadiazole derivative(NBDHEX)can inhibit the activity of glutathione S-transferases(GSTs)and be introduced to conjugate with platinum(Ⅱ)complexes DN603 and DN604 to yield two platinum(Ⅳ)complexes DN603/DN604-NBD.In vitro assays demonstrated that DN603/DN604-NBD could significantly inhibit the proliferation of cisplatin-sensitive A549 and resistant A549/cDDP cancer cells.The uptake of DN603/DN604-NBD in A549/cDDP cells was much higher than that of cisplatin,causing a higher rate of cell apoptosis and a greater ratio of Bax/Bcl-2,the activation of caspase-3 and cleavage of DNA repair enzyme(PARP),inducing the mitochondria-dependent cell apoptosis pathway.DN603/DN604-NBD could induce higher reactive oxygen species(ROS)levels,significantly enhance phosphorylation of histone H2AX on Ser-139(γ-H2AX)fluorescence intensity and cause a greater degree of DNA double-stranded damage.Studies have shown that GSTs kinase GSTP1 was highly expressed in cisplatin-resistant cancer cells.Moreover,DN603/DN604-NBD targeted GSTP1 to suppress its expression level.By using the ROS scavenger NAC and the c-Jun N-terminal kinase(JNK)inhibitor SP600125 in advance,it was found that DN603/DN604-NBD could significantly increase the number of living cells and decrease the phosphorylation levels of JNK and c-Jun.The results indicated that DN603/DN604-NBD could produce higher levels of ROS to activate JNK-mediated signaling pathway,induce apoptosis in tumor cells to overcome cisplatin resistance.All the animal experiments were approved by Animal Ethics Committee of Southeast University(grant No.20210303025).In vivo assays confirmed that DN603/DN604-NBD could inhibit the growth of A549 xenograft tumors with nearly no toxicity and fewer side effects.Taken together,DN603/DN604-NBD are investigated as two potential novel platinum(Ⅳ)prodrug candidates for anticancer therapy.
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