Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Domperidone, a Dopamine Receptor D2 Antagonist, Induces Apoptosis by Inhibiting the ERK/STAT3-Mediated Pathway in Human Colon Cancer HCT116 Cells

  • So Jin Sim (College of Pharmacy, Keimyung University) ;
  • Jeong-Hoon Jang (College of Pharmacy, Daegu Catholic University) ;
  • Joon-Seok Choi (College of Pharmacy, Daegu Catholic University) ;
  • Kyung-Soo Chun (College of Pharmacy, Keimyung University)
  • Received : 2024.03.20
  • Accepted : 2024.04.22
  • Published : 2024.09.01
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Abstract

Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase-3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and N-acetylcysteine treatment mitigated ROS levels and restored cell viability. An in vivo xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.

Keywords

Acknowledgement

This study was supported by the Basic Science Research Program grant (No. 2020R1l1A3066367 to KSC; No. 2018R1D1A1A02050495 and 2021R1A2C1014399 to JSC) from the National Research Foundation (NRF) of the Republic of Korea.

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