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, constructed Tdp1 overexpressing CL187, Top1- or Tdp1- 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.Topoisomerase 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, constructed Tdp1 overexpressing CL187, Top1- or Tdp1- 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, PTE and RE can inhibit the activity of Top1 enzyme and inhibit the DNA damage repair pathway mediated by Top1/Tdp1, and can effectively inhibit colorectal cancer development with low toxicity, thus they have great potential to be developed into a new generation of anti-tumor drugs.
Highlights
Since Wang et al discovered the first protein that can change the topology of DNA in1971 [1,2,3], researchers have extensively studied this DNA topoisomerase and found that, unlike normal cells, DNA topoisomerase shows high levels of expression independent of other factors in tumor cells
We found that PTE and RE can down-regulate the protein content and RNA expression of Topoisomerase 1 (Top1) and tyrosyl-DNA phosphodiesterase 1 (Tdp1), which can be developed as a new generation of Top1 inhibitors
This study found that PTE had better cell permeability than RE, and it could quickly enter the nucleus and mitochondria with abundant Top1 enzymes and Tdp1 enzymes in the cells, and PTE had a higher concentration in these two organelles, enabling a variety of functional enzymes to be exposed to the high concentration of PTE, which was conducive to the corresponding function of PTE
Summary
Since Wang et al discovered the first protein that can change the topology of DNA in1971 [1,2,3], researchers have extensively studied this DNA topoisomerase and found that, unlike normal cells, DNA topoisomerase shows high levels of expression independent of other factors in tumor cells. Inhibiting the activity of DNA topoisomerase can prevent the rapid proliferation of tumor cells. Topoisomerase 1 (Top1) enzyme is an important target of anti-tumor drugs, and Top inhibitors are widely used in clinical practice, the main chemotherapeutic drugs targeting Top were camptothecin (CPT) and its derivatives. CPT-11 s active metabolite SN38 has a strong toxicity in addition to its antitumor effect [6]. With increasing doses, these drugs’ side effects such as diarrhea and neutropenia become serious, even leading to treatment interruption. Tdp has been reported to repair the CPT-induced DNA damage, causing drug resistance in tumor cells. The development of Top1– Tdp dual inhibitors is underway [14,15,16,17,18,19,20]
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