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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