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AMTB, a TRPM8 antagonist, suppresses growth and metastasis of osteosarcoma through repressing the TGFβ signaling

Yujie Liu1, Ao Leng1, Lin Li1

  • 1Department of Orthorpedics,Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, China.

Cell Death & Disease
|April 1, 2022
PubMed

Insights

N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy] -N-(2-thienylmethyl) benzamide hydrochloride (AMTB) inhibits osteosarcoma growth by targeting TRPM8. This TRPM8 antagonist also enhances cisplatin efficacy and suppresses the TGFβ pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Transient receptor potential melastatin-subfamily member 8 (TRPM8) is overexpressed in various cancers, including osteosarcoma, and contributes to tumorigenesis.
  • TRPM8 expression levels in osteosarcoma tissues correlate negatively with patient prognosis, suggesting its role in disease progression.

Purpose of the Study:

  • To investigate the antitumoral effects of N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy] -N-(2-thienylmethyl) benzamide hydrochloride (AMTB), a specific TRPM8 antagonist, on osteosarcoma.
  • To elucidate the underlying molecular mechanisms of AMTB's action and its potential to enhance chemotherapy in osteosarcoma.

Main Methods:

  • In vitro studies using osteosarcoma cell lines treated with AMTB.
  • In vivo experiments utilizing a xenograft mouse model.
  • RNA sequencing analysis to identify molecular pathways affected by AMTB.

Main Results:

  • AMTB significantly suppresses osteosarcoma cell proliferation, metastasis, and induces apoptosis.
  • AMTB treatment enhances the sensitivity of osteosarcoma cells to cisplatin chemotherapy.
  • AMTB antagonizes TRPM8, which is upregulated in osteosarcoma, and inhibits the Transforming Growth Factor β (TGFβ) signaling pathway.

Conclusions:

  • TRPM8 is a potential therapeutic target in osteosarcoma.
  • AMTB demonstrates significant antitumoral activity by inhibiting TRPM8 and the TGFβ pathway, and it can potentiate cisplatin treatment for osteosarcoma.

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