Fentanyl activates ovarian cancer and alleviates chemotherapy-induced toxicity via opioid receptor-dependent activation of EGFR

BMC Anesthesiol. 2022 Aug 23;22(1):268. doi: 10.1186/s12871-022-01812-4.


Background: Fentanyl is an opioid analgesic and is widely used in ovarian cancer patients for pain management. Although increasing evidence has suggested the direct role of fentanyl on cancer, little is known on the effect of fentanyl on ovarian cancer cells.

Methods: Proliferation, migration and apoptosis assays were performed in ovarian cancer cells after fentanyl treatment. Xenograft mouse model was generated to investigate the in vivo efficacy of fentanyl. Combination index was analyzed for the combination of fentanyl and chemotherapeutic drugs. Immunoblotting approach was used to analyze signaling involved in fentanyl's action focusing on EGFR.

Results: Fentanyl at nanomolar concentration does-dependently increased migration and proliferation of a panel of ovarian cancer cell lines. Fentanyl at the same concentrations either did not or stimulated proliferation to a less extent in normal cells than in ovarian cancer cells. Consistently, fentanyl significantly promoted ovarian cancer growth in vivo. The combination of fentanyl with cisplatin or paclitaxel was antagonist in inhibiting cell proliferation. Although fentanyl did not affect cell apoptosis, it significantly alleviated ovarian cancer cell death induced by chemotherapeutic drugs. Mechanistically, fentanyl specifically activated EGFR and its-mediated downstream pathways. Knockdown of EGFR abolished the stimulatory effects of fentanyl on ovarian cancer cells. We finally demonstrated that the activation of EGFR by fentanyl is associated with opioid µ receptor system.

Conclusions: Fentanyl activates ovarian cancer via simulating EGFR signaling pathways in an opioid µ receptor-dependent manner. The activation of EGFR signaling by fentanyl may provide a new guide in clinical use of fentanyl in ovarian cancer patients.

Keywords: Antagonism; EGFR; Fentanyl; Ovarian cancer; µ opioid receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use
  • Animals
  • Antineoplastic Agents*
  • Cell Line, Tumor
  • ErbB Receptors / metabolism
  • ErbB Receptors / therapeutic use
  • Female
  • Fentanyl / pharmacology
  • Fentanyl / therapeutic use
  • Humans
  • Mice
  • Ovarian Neoplasms* / drug therapy
  • Receptors, Opioid / therapeutic use


  • Analgesics, Opioid
  • Antineoplastic Agents
  • Receptors, Opioid
  • EGFR protein, human
  • ErbB Receptors
  • Fentanyl