Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway

Abstract

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.

Mechanism of Pterostilbene-Induced Cell Death in HT-29 Colon Cancer Cells

“…Other research has also confirmed the reduction of colon cancer cell growth exerted by pterostilbene. The time-and dose-dependent growth inhibitory effect of pterostilbene against six different colon cancer cell lines (CL187, COLO205, HCT-8, SW480, LoVo, and HCT-116) was observed in studies performed by Zhang et al [28], and after 48 h treatment with pterostilbene, the IC50 values ranged from 13.82 and 35.73 µM. Furthermore, the results of our study revealed not only inhibition of growth but also a significant time-and dose-dependent reduction in the proliferation rate of HT-29 after incubation with pterostilbene.…”

Phase I Metabolism of Pterostilbene, a Dietary Resveratrol Derivative: Metabolite Identification, Species Differences, Isozyme Contribution, and Further Bioactivation

“…7 More recently, it is reported that PTE exhibited potent antitumor activities against various types of cancers. 8,9 PTE was shown to inhibit tumor cell growth by inducing autophagy and apoptosis, 10 altering cell cycle, 11 and inhibiting tumor cell migration and invasion. 12 In addition, PTE was recognized as a safe and tolerable compound in both animals and humans.…”

“…Similar to resveratrol, PTE showed diverse bioactivities, including anti-inflammatory, antiaging, anti-obesity, anti-steatosis, antidiabetic, and neuroprotective effects . More recently, it is reported that PTE exhibited potent antitumor activities against various types of cancers. , PTE was shown to inhibit tumor cell growth by inducing autophagy and apoptosis, altering cell cycle, and inhibiting tumor cell migration and invasion . In addition, PTE was recognized as a safe and tolerable compound in both animals and humans. , Thus, it is believed that PTE is a health-promoting nutraceutical with guaranteed efficacy and safety profile.…”

Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1

“…Although numerous small molecule TDP1 inhibitors have been reported ( Dyrkheeva et al, 2021 ; Salomatina et al, 2021 ; Zhang et al, 2021 ), the structural basis of their interactions with the enzyme are poorly understood due to a lack of X-ray crystal structures of TDP1 bound to inhibitors. None-the-less, molecular recognition of DNA-containing substrates has been informed by crystal structures of TDP1 with vanadate or tungstate phosphate mimetics bound at the TDP1 catalytic site, as well as with DNA or substrate surrogates ( Figure 1A ) ( Davies et al, 2003 ; 2004 ).…”