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Purpose <p>Breast cancer remains the leading malignancy due to frequent development of acquired resistance to endocrine therapies, which often leads to disease progression and metastasis. Anti-cancer peptides (ACPs) represent a new frontier in targeted cancer therapy due to their selective cytotoxicity, ability to modulate intracellular signaling and reduced systemic toxicity. Marine organisms, particularly sponges, are rich sources of bioactive molecules with promising anticancer properties. This study explores the pro-apoptotic and antioxidant effects of Cyclo(Pro-Tyr), a diketopiperazine isolated from the marine sponge <i>Callyspongia fistularis</i> symbionts against MCF-7 human breast cancer cells, with a focus on mitochondrial-mediated apoptosis.</p> Methods <p>MCF-7 cells were exposed to varying concentrations of Cyclo(Pro-Tyr) and evaluated for cytotoxicity (MTT, Neutral Red assays), apoptosis (AO/EB, PI, DAPI staining), Reactive Oxygen Species (ROS) generation (DCFH-DA), and disruption of mitochondrial membrane potential (Rhodamine 123). Apoptotic gene expression (Bax, Bcl-2, Caspase-3, -9) was assessed via qPCR analysis. Flow cytometry (Annexin V-FITC/PI) was used to quantify apoptotic populations. In silico docking was performed to explore interactions between Cyclo(Pro-Tyr) and apoptosis-related proteins.</p> Results <p>Cyclo(Pro-Tyr) exhibited dose-dependent cytotoxicity with an IC₅₀ of ~ 84.55 µM and induced significant mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, increased ROS levels, and prominent nuclear condensation. A marked shift toward late apoptotic populations was observed in flow cytometric analysis. qPCR revealed suppression of anti-apoptotic <i>Bcl-2</i> and upregulation of pro-apoptotic <i>Bax</i>, <i>Caspase-3</i>, and <i>Caspase-9</i> mRNA expressions. Additionally, molecular docking studies supported high binding affinities of Cyclo(Pro-Tyr) to these apoptotic target proteins. Antioxidant assays showed moderate radical scavenging potential, supporting dual activity.</p> Conclusion <p>Cyclo(Pro-Tyr) induces intrinsic apoptosis in MCF-7 cells through oxidative stress, loss of mitochondrial membrane potential, and modulation of pro-apoptotic signaling pathways. These findings highlight its potential as a promising marine-derived lead molecule for breast cancer therapy.</p>

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Dual Redox-Apoptotic Mechanism of Cyclo(Pro-Tyr): A Marine-Derived Anticancer Peptide Targeting Mitochondrial Dysfunction in Breast Cancer Cells

  • 期刊论文

  • 发表日期：

    2026年4月17日

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  • Shana Balachandran,
  • Madan Kumar Arumugam

摘要

Purpose

Breast cancer remains the leading malignancy due to frequent development of acquired resistance to endocrine therapies, which often leads to disease progression and metastasis. Anti-cancer peptides (ACPs) represent a new frontier in targeted cancer therapy due to their selective cytotoxicity, ability to modulate intracellular signaling and reduced systemic toxicity. Marine organisms, particularly sponges, are rich sources of bioactive molecules with promising anticancer properties. This study explores the pro-apoptotic and antioxidant effects of Cyclo(Pro-Tyr), a diketopiperazine isolated from the marine sponge Callyspongia fistularis symbionts against MCF-7 human breast cancer cells, with a focus on mitochondrial-mediated apoptosis.

Methods

MCF-7 cells were exposed to varying concentrations of Cyclo(Pro-Tyr) and evaluated for cytotoxicity (MTT, Neutral Red assays), apoptosis (AO/EB, PI, DAPI staining), Reactive Oxygen Species (ROS) generation (DCFH-DA), and disruption of mitochondrial membrane potential (Rhodamine 123). Apoptotic gene expression (Bax, Bcl-2, Caspase-3, -9) was assessed via qPCR analysis. Flow cytometry (Annexin V-FITC/PI) was used to quantify apoptotic populations. In silico docking was performed to explore interactions between Cyclo(Pro-Tyr) and apoptosis-related proteins.

Results

Cyclo(Pro-Tyr) exhibited dose-dependent cytotoxicity with an IC₅₀ of ~ 84.55 µM and induced significant mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, increased ROS levels, and prominent nuclear condensation. A marked shift toward late apoptotic populations was observed in flow cytometric analysis. qPCR revealed suppression of anti-apoptotic Bcl-2 and upregulation of pro-apoptotic Bax, Caspase-3, and Caspase-9 mRNA expressions. Additionally, molecular docking studies supported high binding affinities of Cyclo(Pro-Tyr) to these apoptotic target proteins. Antioxidant assays showed moderate radical scavenging potential, supporting dual activity.

Conclusion

Cyclo(Pro-Tyr) induces intrinsic apoptosis in MCF-7 cells through oxidative stress, loss of mitochondrial membrane potential, and modulation of pro-apoptotic signaling pathways. These findings highlight its potential as a promising marine-derived lead molecule for breast cancer therapy.