Synergistic suppressive effects on triple-negative breast cancer by the combination of JTC-801 and sodium oxamate

Chih-Yang Wang; Do Thi Minh Xuan; Pei-Hsuan Ye; Chung-Yen Li; Gangga Anuraga; Hoang Dang Khoa Ta; Ming-Derg Lai; Hui-Ping Hsu

Synergistic suppressive effects on triple-negative breast cancer by the combination of JTC-801 and sodium oxamate

Am J Cancer Res. 2023 Oct 15;13(10):4661-4677. eCollection 2023.

Authors

Chih-Yang Wang^{1

2

3}, Do Thi Minh Xuan¹, Pei-Hsuan Ye⁴, Chung-Yen Li⁵, Gangga Anuraga^{2

6}, Hoang Dang Khoa Ta², Ming-Derg Lai^{4

5}, Hui-Ping Hsu⁷

Affiliations

¹ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
² Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University Taipei 11031, Taiwan.
³ TMU Research Center of Cancer Translational Medicine, Taipei Medical University Taipei 11031, Taiwan.
⁴ Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
⁵ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
⁶ Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University East Java, Surabaya 60234, Indonesia.
⁷ Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.

PMID: 37970352
PMCID: PMC10636693

Abstract

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to the limited targeted therapies available at present. Cancer cells preferentially use glycolysis as their primary source of energy, characterized by increased glucose uptake and lactate production. JTC-801, a nociception/orphanin FQ opioid peptide (NOP) receptor antagonist, was reported to suppress the opioid receptor-like1 (ORL1) receptor/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor (NF)-κB-mediated carbonic anhydrase 9 (CA9) signaling pathway. Sodium oxamate is an inhibitor of gluconeogenesis and a glycolysis inhibitor, as a competitive lactate dehydrogenase A (LDHA) inhibitor, which also produces tumor suppression due to loss of LDHA activity. However, the roles of opioid analgesic drugs (e.g., JTC-801) and glycolysis inhibitors (e.g., sodium oxamate) in TNBC have not fully been explored. Meanwhile, concurrent treatment with JTC-801 and sodium oxamate may cause synergistic anticancer effects in a TNBC model. In the present study, the combination of JTC-801 and sodium oxamate triggered cell death in the TNBC MDA MB-231 cell line. RNA-sequencing data revealed potential genes in the crosstalk between JTC-801 and sodium oxamate including ALDOC, DDIT4, DHTKD1, EIF6, ENO1, ENO3, FOXK1, FOXK2, HIF1A, MYC, PFKM, PFKP, PPARA, etc. The combination of JTC-801 and sodium oxamate provides a novel potential therapeutic strategy for TNBC patients via downregulating cell cycle- and amino acid metabolism-related pathways such as "Cell cycle-the metaphase checkpoint", "(L)-tryptophan pathways and transport", and "Glutamic acid pathway". Collectively, the present study demonstrated that the synergistic effect of co-treatment with JTC-801 and sodium oxamate significantly suppressed tumor growth and played a crucial role in tumor development, and in turn may serve as potential synergistic drugs for TNBC.

Keywords: JTC-801; Triple-negative breast cancer; cell metabolism; glycolysis; sodium oxamate; synergistic effect.