Rosmarinic Acid as a Candidate in a Phenotypic Profiling Cardio-/Cytotoxicity Cell Model Induced by Doxorubicin

Abstract

Advances in cancer treatment have led to significant improvements in long-term survival in many types of cancer, but heart dysfunction and heart failure, associated with cancer treatment, have also increased. Anthracyclines are the main cause of this type of cardiotoxicity. In this study, we describe a combined experimental and cell morphology analysis approach for the high-throughput measurement and analysis of a cardiomyocyte cell profile, using partial least square linear discriminant analysis (PLS-LDA) as the pattern recognition algorithm. When screening a small-scale natural compound library, rosmarinic acid (RosA), as a candidate drug, showed the same cardioprotective effect as the positive control. We investigated the protective mechanism of RosA on a human cardiomyocyte cell line (AC16) and human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We showed that RosA pretreatment suppressed doxorubicin (Dox)-induced cell apoptosis and decreased the activity of caspase-9. RosA promotes the expression of Heme oxygenase-1 (HO-1) and reduces the production of reactive oxygen species (Ros), which is induced by Dox. Meanwhile, it can also promote the expression of cardiac-development-related protein, including histone deacetylase 1 (HDAC1), GATA binding protein 4 (GATA4) and troponin I3, cardiac type (CTnI). Collectively, our data support the notion that RosA is a protective agent in hiPSC-CMs and has the potential for therapeutic use in the treatment of cancer therapy-related cardiac dysfunction and heart failure.

Image-based profiling for drug discovery: due for a machine-learning upgrade?

“…A high-throughput in vitro phenotypic profiling for toxicity prediction (HIPPTox) system predicted pulmonotoxicity more accurately than cell viability assays in human lung cell lines 90 . Image-based profiling identified rosmarinic acid as a candidate with cardioprotective effects against the toxicity of doxorubicin 91 . This approach also revealed the toxic effects of bisphenol A and its analogues on a testicular cell co-culture model by simultaneously measuring multiple adverse end points such as changes to nuclear morphology and cytoskeletal structure 92 .…”

Journey of Rosmarinic Acid as Biomedicine to Nano-Biomedicine for Treating Cancer: Current Strategies and Future Perspectives

“…The stimulation of heme oxygenase-1 (HO-1), which reduces the production of reactive oxygen species, promoted the expression of various proteins such as histone deacetylase, GATA binding protein 4, and troponin13. These findings suggested the therapeutic benefit of RA with special reference to the cancer therapy-related cardiac dysfunction [59].…”

Molecular Pathways of Rosmarinic Acid Anticancer Activity in Triple-Negative Breast Cancer Cells: A Literature Review

“…On the contrary, there is evidence that the antioxidant activity of Rosmarinic Acid can limit the toxicity exerted by chemotherapy in human HL-60 promyelocytic leukemia cells [ 103 ]. Additionally, in vivo studies have shown that Rosmarinic Acid decreased the hepatic and renal toxicity induced by methotrexate, as well as the cardiotoxicity of doxorubicin [ 39 , 104 , 105 ]. In a randomized, placebo-controlled trial in BC patients, oral intake of Prunella vulgaris L., rich in Rosmarinic Acid, inhibited chemotherapy (taxanes) side effects, namely neutrophil-reduced fever and anemia [ 106 ].…”