Insights into mechanisms and promising triple negative breast cancer therapeutic potential for a water-soluble ruthenium compound Journal Article
| Authors: | Nayeem, N.; Sauma, S.; Ahad, A.; Rameau, R.; Kebadze, S.; Bazett, M.; Park, B. J.; Casaccia, P.; Prabha, S.; Hubbard, K.; Contel, M. |
| Article Title: | Insights into mechanisms and promising triple negative breast cancer therapeutic potential for a water-soluble ruthenium compound |
| 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. © 2024 American Chemical Society. |
| Keywords: | immunohistochemistry; signal transduction; protein kinase b; controlled study; human cell; histopathology; drug efficacy; drug potentiation; monotherapy; nonhuman; cell proliferation; animal cell; mouse; animal tissue; apoptosis; animal experiment; animal model; in vivo study; caspase 3; in vitro study; tumor xenograft; angiogenesis; phosphatidylinositol 3 kinase; protein p53; cancer therapy; drug accumulation; mammalian target of rapamycin; reactive oxygen metabolite; blood cell count; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; antiangiogenic activity; cell invasion; mitochondrion; migration inhibition; in vivo; olaparib; ruthenium derivative; ruthenium compounds; water solubility; mechanisms; disorders of mitochondrial functions; triple negative breast cancer; akt signaling; membrane potential; human; female; article; drug dna interaction; mda-mb-231 cell line; platelet endothelial cell adhesion molecule 1; protein expression level; chemotherapeutics |
| Journal Title: | ACS Pharmacology & Translational Science |
| Volume: | 7 |
| Issue: | 5 |
| ISSN: | 2575-9108 |
| Publisher: | American Chemical Society |
| Date Published: | 2024-05-10 |
| Start Page: | 1364 |
| End Page: | 1376 |
| Language: | English |
| DOI: | 10.1021/acsptsci.4c00020 |
| PROVIDER: | scopus |
| PMCID: | PMC11092013 |
| PUBMED: | 38751641 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
