Exploring the in vitro effects of Helichrysum petiolares for its potential to provide cardioprotective benefits against Doxorubicin toxicity

Introduction: The increasing prevalence of triple-negative breast cancer (TNBC) in sub-Saharan Africa (SSA) has led to a greater reliance on doxorubicin (Dox) as a primary chemotherapeutic agent. However, its nonspecific cytotoxicity contributes to severe cardiotoxic effects, exacerbating the region's already high burden of cardiovascular disease (CVD). Given the intricate bidirectional relationship between cancer and CVD, and because cardioprotective agents are limited and not locally available, the development of cardioprotective interventions that mitigate Dox-induced toxicity without compromising its anticancer efficacy is critical. Helichrysum petiolare (H. petiolare), a medicinal plant traditionally used for cardiovascular health in Southern Africa, has demonstrated potential as a cardioprotective agent. To our knowledge, this study was the first to investigate its antioxidant properties, protective effects against Dox-induced oxidative stress in cardiomyocytes, and its influence on Dox cytotoxicity in breast cancer cells. Methods: H9C2 cardiomyocytes, MCF-12A non-cancerous breast epithelial cells, and MDA-MB-231 TNBC cells were exposed to 12.5 μg/mL H. petiolare methanol extract or Dox for three hours, followed by inverse or combination treatments for 24 hours under standard cell culture conditions. Antioxidant capacity was evaluated using the 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) assay, while metabolic activity was assessed via the Water-Soluble Tetrazolium-1 (WST-1) assay. Intracellular reactive oxygen species (ROS) levels were quantified using the 2',7'-Dichlorofluorescin (DCF) assay. Western blot analysis was performed to determine mitochondrial protein expression, specifically superoxide dismutase 2 (SOD2) and cytochrome c. Results: The H. petiolare methanol extract exhibited potent antioxidant activity (IC50 = 4.42 μg/mL), surpassing ascorbic acid (IC50 = 4.78 μg/mL). Pretreatment with Dox, followed by 12.5 μg/mL H. petiolare methanol extract significantly attenuated Dox-induced cardiotoxicity in H9C2 cells (p<0.0001, n=5), by reducing oxidative stress and with markedly reduced SOD2 expression (p<0.01, n=3). Additionally, the extract in combination and post Dox-insult conferred cytoprotective effects (p=0.1276 and p=0.7922, n=3) in MCF-12A cells, while also preserving Dox's cytotoxic efficacy in MDA-MB-231 TNBC cells (p<0.001, n=4). Additionally, it maintained mitochondrial integrity, as indicated by sustained cytochrome c expression levels. Conclusion: These laboratory-based findings suggest that H. petiolare possesses significant cardioprotective potential against chemotherapy-induced toxicity. By mitigating oxidative stress and preserving mitochondrial function, it may serve as a natural adjunct therapy to reduce the cardiotoxic effects of Dox without compromising its anticancer activity. Further in vivo studies, pharmacokinetic profiling, and mechanistic investigations are warranted to elucidate its full therapeutic potential in the field of Cardio-Oncology.

Grantor dc:publisher

Stellenbosch : Stellenbosch University

Year dc:date.issued

2026

Author dc:creator

• Bredenkamp, Jhade Cameron

Advisor dc:contributor.advisor

• Sishi, Balindiwe J. N.

Language dc:language.iso

en

Repository record dc:identifier.uri

https://scholar.sun.ac.za/handle/10019.1/135953

OAI identifier oai:identifier

oai:scholar.sun.ac.za:10019.1/135953