关键词: 凋亡, 雷公藤甲素(TPL), 热休克蛋白90(Hsp90), 多肽偶联药物, 协同作用

Abstract: Objective To investigate the anti-tumor effect of the peptide conjugate drug TPL-P7, which is a dual-targeting Peptide 7(P7) and triptolide (TPL), and targeted at HSP90. Methods In the test system of non-small cell lung cancer cell line A549, the cell viability was evaluated by sulforhodamine B (SRB) assay after 48 hours of treatment with TPL alone or in combination with P7. Furthermore, the apoptosis was evaluated by flow cytometry to explore the synergistic effect of the targeting peptide P7 and triptolide. The anti-tumor activity of the peptide conjugate drug TPL-P7 was evaluated by SRB assay. Subsequently, an in vivo anti-tumor activity of TPL-P7 was assessed in the subcutaneous xenograft tumor model of non-small cell lung cancer cell line A549. Result TPL and P7 combination led to a significant left shift in the cell survival curve of TPL, indicating that the P7 significantly increased the sensitivity to TPL. The equivalent line graph showed that the dose ratios of P7 combined with TPL were 2∶1, 1∶1, and 1∶2, all of which were below the equivalent line, and the optimal ratio point was 1∶1. Flow cytometry results demonstrated that combination significantly promoted apoptosis, which was higher than that of the TPL single drug group (P＜0.05). TPL-P7 exhibited significant tumor-killing effects in both A549 and PANC-1 cells, with IC₅₀ values of 14.0 μmol/L and 2.8 μmol/L respectively. After four weeks of administration, the tumor inhibitory rate of TPL-P7 was as 60%, significantly different from the equal-molar dose of TPL(P＜0.05).ConclusionsThere are a synergistic killing effect of targeting peptide P7 and triptolide. The peptide conjugate drug TPL-P7 exerts an anti-tumor activity both in vitro and in vivo with low toxic side effects.

Key words: apoptosis, triptolide (TPL), heat shock protein 90 (Hsp90), peptide-drug conjugate, synergy