Phenylethanol glycosides from Herba Cistanche improve the hypoxic tumor microenvironment and enhance the effects of oxaliplatin via the HIF‑1α signaling pathway

Mol Med Rep. 2021 Jul;24(1):517. doi: 10.3892/mmr.2021.12156. Epub 2021 May 20.

Abstract

Liver cancer is one of the most common types of malignant tumor, and is characterized by high malignancy, rapid progression, high morbidity and mortality. Oxaliplatin (OXA) has been reported to have marked efficiency against advanced liver cancer with tolerable toxicity. In solid tumors, the hypoxic microenvironment promotes epithelial‑mesenchymal transition (EMT), which can also induce drug resistance of liver cancer to platinum drugs. Herba Cistanche (Cistanche tubulosa) has been frequently used in traditional Chinese medicine and the phenylethanol glycosides from Herba Cistanche (CPhGs) are the major active components. The present study aimed to investigate the effects of CPhGs on viability, apoptosis, migration and invasion of liver cancer cells. HepG2 liver cancer cells were divided into the control, DMSO, CoCl2, OXA, OXA + CoCl2 and CPhGs + OXA + CoCl2 groups. Subsequently, reverse transcription‑quantitative PCR and western blot analysis were performed to determine the expression levels of hypoxia‑inducible factor 1α (HIF‑1α), lysyl oxidase‑like 2 (LOXL2) and EMT‑related genes and proteins (i.e., E‑cadherin and Twist), in order to investigate the effects of CPhGs on liver cancer. The results demonstrated that CPhGs could enhance the effects of OXA on liver cancer, and inhibit the migration, invasion and apoptotic rate of liver cancer cells. Additionally, CPhGs treatment effectively induced downregulation of HIF‑1α, LOXL2 and Twist, and upregulation of E‑cadherin. The present findings indicated that CPhGs triggered a significant increase in sensitivity to OXA and suppression of hypoxia‑induced EMT in liver cancer by inhibiting the HIF‑1α signaling pathway. Therefore, CPhGs may be considered an effective platinum drug sensitizer, which could improve chemotherapeutic efficacy in patients with liver cancer.

Keywords: HIF‑1α signaling pathway; epithelial‑mesenchymal transition; hypoxia; liver cancer; phenylethanol glycosides from Herba Cistanche.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Survival
  • Cistanche / chemistry*
  • Glycosides / pharmacology*
  • Hep G2 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Liver Neoplasms / genetics
  • Oxaliplatin / pharmacology*
  • Phenylethyl Alcohol / pharmacology*
  • Plant Extracts / pharmacology*
  • Signal Transduction / drug effects*
  • Tumor Hypoxia / drug effects*
  • Tumor Microenvironment / drug effects*
  • Up-Regulation / drug effects

Substances

  • Glycosides
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Plant Extracts
  • Oxaliplatin
  • Phenylethyl Alcohol

Grants and funding

The present study was supported by the Xinjiang Key Laboratory of Natural Drug Active Components and Drug Release Technology (grant no. XJDX1713), the Reserve Candidate Project for the Leader of Scientific and Technological Innovation in Xinjiang Uygur Autonomous Region (grant no. 2019XS14), the National Natural Science Foundation of China (grant no. 81860735) and the Bethune Charitable Foundation ‘Bethune·Quest-construction of pharmaceutical scientific research capacity’ (grant no. B-19-H-20200622).