Rosmarinic Acid Potentiates Cytotoxicity of Cisplatin against Colorectal Cancer Cells by Enhancing Apoptotic and Ferroptosis

Author:

Huang Jhen-Yu1,Hsu Ta-Wen23,Chen Yu-Ru14,Kao Shao-Hsuan15ORCID

Affiliation:

1. Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung 402306, Taiwan

2. Division of Colorectal Surgery, Buddhist Tzu Chi Medical Foundation, Dalin Tzu Chi Hospital, Chiayi 622401, Taiwan

3. School of Medicine, Tzu Chi University, Hualien 970374, Taiwan

4. Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402306, Taiwan

5. Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402306, Taiwan

Abstract

Rosmarinic acid (RA) has demonstrated anticancer effects on several types of malignancies. However, whether RA promotes the anticancer effect of cisplatin on colorectal cancer cells remains sketchy. This study aimed to explore whether RA potentiates the cytotoxicity of cisplatin against colon cancer cells and the underlying mechanism. Cell viability, cell cycle progression, and apoptosis was evaluated using sulforhodamine B (SRB) assay, flow cytometric analysis, and propidium iodide/Annexin V staining, respectively. Western blotting was utilized to analyze signaling pathways. Our findings showed that RA significantly enhanced the inhibitory effect on cell viability and the induction of apoptosis on the colon cancer cell lines DLD-1 and LoVo. Signaling cascade analysis revealed that the combination of RA and cisplatin jointly induced Bax and caspase activation while downregulating Bcl-2, glutathione peroxidase 4 (GPX4), and SLC7A11 in DLD-1 cells. Moreover, caspase inhibitor and ferroptosis inhibitor significantly reversed the inhibition of cell viability in response to RA combined with cisplatin. Collectively, these findings demonstrate that RA enhances the cytotoxicity of cisplatin against colon cancer cells, attributing to the promotion of apoptosis and ferroptosis.

Funder

Buddhist Tzu Chi Medical Foundation, Dalin Tzu Chi Hospital

Publisher

MDPI AG

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