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Natural small-molecules reverse Xeroderma Pigmentosum Complementation Group C (XPC) deficient-mediated

Ruihong Chen1, Hang Hong Lo2, Chenxu Yang2

  • 1Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China; Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology
|January 12, 2024
PubMed
Abstract

Insights

XPC gene deficiency contributes to drug resistance in renal cancer. Six natural compounds were found to reverse this resistance by upregulating the XPC gene, offering potential new therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Renal cancer exhibits resistance to conventional therapies like radiotherapy and chemotherapy.
  • The role of the XPC gene in renal cancer drug resistance was previously unknown, despite its association with drug resistance in other cancers.
  • Natural small molecules are increasingly used in combination therapy to enhance drug sensitivity and reduce side effects in cancer treatment.

Purpose of the Study:

  • To investigate the correlation between XPC gene deficiency and drug resistance in renal cancer.
  • To identify natural small molecules capable of reversing renal cancer drug resistance by upregulating XPC expression.

Main Methods:

  • Immunohistochemistry (IHC) and TCGA database analysis to assess XPC expression in renal tumors and its correlation with clinical data.
  • Establishment of XPC-knockdown (XPC-KD) renal cancer cell models to screen for XPC gene enhancers from 134 natural compounds.
  • Validation of identified enhancers using MTT cytotoxicity assays in combination with FDA-approved drugs.
  • Mechanistic studies including gene profiling, ROS detection, and cell imaging to elucidate the drug resistance pathway.

Main Results:

  • XPC gene expression was significantly lower in renal cancer tissues compared to adjacent tissues, particularly in advanced stages (Stage IV) with metastasis.
  • Six natural small molecules (tectorigenin, pinostilbene, d-pinitol, polygalasaponin F, atractylenolide III, and astragaloside II) were identified as potent enhancers of XPC expression.
  • Combination therapy with these natural compounds and FDA-approved drugs demonstrated increased sensitivity in XPC-KD renal cancer cells.
  • The GSTP1/ROS axis was identified as a key mechanism activated in drug-resistant XPC-KD renal cancer cells.

Conclusions:

  • XPC gene deficiency is linked to drug resistance in renal cancer, mediated by the GSTP1/ROS axis.
  • The six identified natural small molecules effectively reverse drug resistance by upregulating XPC expression.
  • These natural compounds hold promise as adjuvant therapies to overcome drug resistance in renal cancer.
Keywords:
Drug-resistanceGSTP1Natural small-moleculesRenal cancerXPC

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