Abstract

Simple SummaryTyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs the stalled Topoisomerase 1 (Top1)-DNA covalent complex. It is conceivable that Tdp1 inhibitors could act synergistically with Top1 inhibitors to enhance the effect of Top1 poisons. This study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two proteins by binding to their active center. PTE and RE could inhibit the proliferation of various colorectal cancer cells and decrease Top1 and Tdp1 contents and mRNA expression in wild-type, constructedTdp1 overexpressing CL187,Top1- orTdp1- silenced CL187 cell lines. PTE exhibited better antitumor activity and safety in subcutaneous CL187 transplantion model and orthotopic transplantation model. PTE had no significant inhibitory effect on non-tumor cell proliferation in vitro and would not induce damage to liver, kidney, and other major organs.AbstractTopoisomerase 1 (Top1) inhibitor is an effective anticancer drug, but several factors limit its clinical application such as drug inactivation, tyrosyl-DNA phosphodiesterase 1 (Tdp1)-mediated tumor drug resistance, and its toxicity. Our previous study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two proteins by binding to their active center. PTE and RE could inhibit the proliferation of various colorectal cancer cells, induce cell apoptosis, and make cell cycle stay in G2/M phase in vitro. PTE and RE could decrease Top1 and Tdp1 contents and mRNA expression in wild-type, constructedTdp1 overexpressing CL187,Top1- orTdp1- silenced CL187 cell lines. PTE exhibited excellent antitumor activity in subcutaneous CL187 transplantation model (TGI = 79.14 ± 2.85%, 200 mg/kg, i.p.) and orthotopic transplantation model (TGI = 76.57 ± 6.34%, 100 mg/kg, i.p.; TGI = 72.79 ± 4.06%, 500 mg/kg, i.g.) without significant toxicity. PTE had no significant inhibitory effect on non-tumor cell proliferation in vitro and would not induce damage to liver, kidney, and other major organs. Overall