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The anticancer effect of PQ1 in the MMTV-PyVT mouse model
Stephanie N Shishido1, Adélaïde Delahaye, Amanda Beck
1Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS.
Abstract:
Animal models are commonly used to analyze the mechanism of carcinogenesis as well as the development and screening of potent drugs. Here the transgenic strain FVB/N-Tg(MMTV-PyVT)634Mul/J (also known as PyVT) was used as a model system for measuring tumor burden, drug sensitivity, and metastasis of mammary carcinomas. Loss of gap junctional intercellular communication and the down regulation of connexin expression are characteristic of neoplastic cells. The substituted quinoline, 6-methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3-trifluoromethyl-phenyloxy)quinolone (PQ1), has been shown to restore GJIC and increase connexin expression in breast cancer cell lines while not affecting normal mammary cells, suggesting that it may provide effective anticancer treatment with less detrimental effects. The PyVT spontaneous mammary tumor mouse model was used to determine the biological and histological effects of PQ1 on tumorigenesis and metastasis at three stages of development: Pretumor, early tumor and late tumor formation. Treatment with PQ1 at all three stages of development significantly reduced tumor growth. PQ1 treatment further increased Cx43 expression during pre- and early-tumor formation, while it prevented an increase in Cx46 expression during late stage tumor formation. This study shows that Cx43 expression and neoplastic cellular growth are inversely related, but that PQ1 can alter tumor growth through targeting gap junction proteins to prove clinical efficacy in the treatment of spontaneous mammary tumors.
Insights
The drug PQ1 effectively reduced mammary tumor growth and metastasis in mice by restoring gap junction communication. PQ1 targets gap junction proteins, showing promise for treating spontaneous mammary tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Animal models are crucial for studying cancer mechanisms and drug development.
- Loss of gap junctional intercellular communication (GJIC) and connexin downregulation characterize neoplastic cells.
- The transgenic FVB/N-Tg(MMTV-PyVT)634Mul/J (PyVT) mouse model is used for mammary carcinoma research.
Purpose of the Study:
- To evaluate the biological and histological effects of PQ1 on mammary tumorigenesis and metastasis in the PyVT mouse model.
- To determine PQ1's efficacy across different stages of tumor development: pretumor, early tumor, and late tumor formation.
- To investigate PQ1's impact on connexin expression (Cx43 and Cx46) and its relationship with tumor growth.
Main Methods:
- Utilized the PyVT spontaneous mammary tumor mouse model.
- Administered PQ1 at three distinct developmental stages of mammary tumors.
- Assessed tumor burden, metastasis, and histological changes.
- Quantified the expression levels of Cx43 and Cx46.
Main Results:
- PQ1 treatment significantly reduced tumor growth at all three developmental stages.
- PQ1 increased Cx43 expression during pre- and early-tumor formation.
- PQ1 prevented an increase in Cx46 expression during late-stage tumor formation.
- A significant inverse relationship was observed between Cx43 expression and neoplastic cellular growth.
Conclusions:
- PQ1 demonstrates significant efficacy in reducing spontaneous mammary tumor growth and metastasis.
- PQ1's mechanism involves restoring GJIC and modulating connexin expression, particularly Cx43.
- PQ1 shows potential as a therapeutic agent for mammary carcinomas with reduced side effects on normal cells.
