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Insights into Mechanisms and Promising Triple Negative Breast Cancer Therapeutic Potential for a Water-Soluble
Nazia Nayeem1,2,3, Sami Sauma3,4,5, Afruja Ahad1,2,3,6
1Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States.
Abstract:
Triple negative breast cancer (TNBC) represents a subtype of breast cancer that does not express the three major prognostic receptors of human epidermal growth factor receptor 2 (HER2), progesterone (PR), and estrogen (ER). This limits treatment options and results in a high rate of mortality. We have reported previously on the efficacy of a water-soluble, cationic organometallic compound (Ru-IM) in a TNBC mouse xenograft model with impressive tumor reduction and targeted tumor drug accumulation. Ru-IM inhibits cancer hallmarks such as migration, angiogenesis, and invasion in TNBC cells by a mechanism that generates apoptotic cell death. Ru-IM displays little interaction with DNA and appears to act by a P53-independent pathway. We report here on the mitochondrial alterations caused by Ru-IM treatment and detail the inhibitory properties of Ru-IM in the PI3K/AKT/mTOR pathway in MDA-MB-231 cells. Lastly, we describe the results of an efficacy study of the TNBC xenografted mouse model with Ru-IM and Olaparib monotherapy and combinatory treatments. We find 59% tumor shrinkage with Ru-IM and 65% with the combination. Histopathological analysis confirmed no test-article-related toxicity. Immunohistochemical analysis indicated an inhibition of the angiogenic marker CD31 and increased levels of apoptotic cleaved caspase 3 marker, along with a slight inhibition of p-mTOR. Taken together, the effects of Ru-IM in vitro show similar trends and translation in vivo. Our investigation underscores the therapeutic potential of Ru-IM in addressing the challenges posed by TNBC as evidenced by its robust efficacy in inhibiting key cancer hallmarks, substantial tumor reduction, and minimal systemic toxicity.
Insights
A novel organometallic compound, Ru-IM, effectively reduced triple-negative breast cancer (TNBC) tumors in mice by inhibiting key cancer hallmarks. This compound demonstrated significant tumor shrinkage with minimal toxicity, showing therapeutic promise for TNBC treatment.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) lacks expression of ER, PR, and HER2, limiting therapeutic options and leading to poor outcomes.
- Existing treatments for TNBC are insufficient, highlighting the need for novel therapeutic strategies.
- Previous studies showed the efficacy of the organometallic compound Ru-IM in a TNBC mouse model.
Purpose of the Study:
- To investigate the mitochondrial alterations induced by Ru-IM in TNBC cells.
- To elucidate the inhibitory effects of Ru-IM on the PI3K/AKT/mTOR pathway.
- To evaluate the in vivo efficacy of Ru-IM, alone and in combination with Olaparib, in a TNBC xenograft model.
Main Methods:
- Treatment of MDA-MB-231 cells and a TNBC mouse xenograft model with Ru-IM.
- Analysis of mitochondrial alterations and PI3K/AKT/mTOR pathway activity.
- Assessment of tumor volume, histopathology, and immunohistochemical markers (CD31, cleaved caspase 3, p-mTOR).
Main Results:
- Ru-IM treatment led to significant tumor shrinkage (59%) in the TNBC xenograft model, with combination therapy showing 65% shrinkage.
- Histopathological analysis revealed no treatment-related toxicity.
- Immunohistochemistry confirmed inhibition of angiogenesis (CD31), increased apoptosis (cleaved caspase 3), and partial inhibition of p-mTOR.
Conclusions:
- Ru-IM demonstrates significant anti-cancer effects in vitro and in vivo by targeting key cancer hallmarks and the PI3K/AKT/mTOR pathway.
- Ru-IM exhibits substantial tumor reduction efficacy in TNBC models with a favorable safety profile.
- The findings underscore the therapeutic potential of Ru-IM for treating triple-negative breast cancer.
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