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Dissecting the Mechanism of Action of Spiperone-A Candidate for Drug Repurposing for Colorectal Cancer

Annamaria Antona1, Marco Varalda1, Konkonika Roy2

  • 1Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy.

Cancers
|February 15, 2022
PubMed

Insights

The antipsychotic drug spiperone shows promise for treating colorectal cancer (CRC) by inducing cancer cell death and disrupting calcium homeostasis. This drug repurposing strategy offers a potential new therapy with minimal toxicity to healthy cells.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Colorectal cancer (CRC) remains a leading cause of cancer-related deaths, with high rates of recurrence and metastasis.
  • Drug repurposing offers a cost-effective alternative to traditional drug discovery for novel cancer therapies.
  • Antipsychotic drugs have demonstrated potential antitumor activities, warranting further investigation.

Purpose of the Study:

  • To investigate the mechanism of action of the antipsychotic drug spiperone in colorectal cancer (CRC).
  • To evaluate spiperone's efficacy and safety in preclinical models of CRC, including stem-like cells.
  • To identify the molecular pathways targeted by spiperone in CRC treatment.

Main Methods:

  • Assessed spiperone's effects on CRC cell proliferation, cell cycle, and apoptosis.
  • Analyzed intracellular calcium (Ca2+) dynamics and endoplasmic reticulum (ER) Ca2+ release.
  • Utilized RNA sequencing to identify molecular changes, including unfolded protein response (UPR) and ER stress.
  • Performed lipidomic analysis to investigate alterations in lipid metabolism, particularly sphingolipids.

Main Results:

  • Spiperone reduced the clonogenic potential of CRC stem-like cells (CRC-SCs) and induced cell cycle arrest and apoptosis in differentiated and stem-like CRC cells.
  • Clinically relevant concentrations of spiperone exhibited negligible toxicity to non-neoplastic cells.
  • Spiperone triggered massive phospholipase C (PLC)-dependent ER Ca2+ release, disrupting ER Ca2+ homeostasis.
  • RNA sequencing revealed activation of UPR, ER stress, apoptosis, and IRE1-dependent decay of mRNA (RIDD).
  • Lipidomic analysis indicated significant alterations in lipid profiles, especially sphingolipids, and observed damage to the Golgi apparatus.

Conclusions:

  • Spiperone demonstrates potential as an effective therapeutic agent for colorectal cancer (CRC).
  • ER stress induction and lipid metabolism alteration are identified as key druggable pathways targeted by spiperone in CRC.
  • Drug repurposing of spiperone presents a promising strategy for novel CRC treatment.
Keywords:
Golgicancer stem cellscolorectal cancerendoplasmic reticulum stressintracellular calciumlipid metabolismmitochondriaphospholipase Cpsychotropic drugsrepurposing

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