Listeriolysin O Synergizes with Cisplatin and Carfilzomib to Promote Apoptosis in Ovarian Cancer by Modulating Bcl-2 and Bax Expression

Ghasemzadeh, Navid; Zavar Reza, Javad; Fatehi Marj, Amir Hossein; Moradi, Moein; Takhtechian, Hooriya; Zarei, Sadegh

doi:10.22034/jcrph.2025.558770.1014

Listeriolysin O Synergizes with Cisplatin and Carfilzomib to Promote Apoptosis in Ovarian Cancer by Modulating Bcl-2 and Bax Expression

Document Type : Original Article

Authors

Navid Ghasemzadeh ¹

Javad Zavar Reza ²

Amir Hossein Fatehi Marj ³

Moein Moradi ⁴

Hooriya Takhtechian ⁴

Sadegh Zarei ⁴

¹ Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran

² Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran

³ Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

⁴ Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

10.22034/jcrph.2025.558770.1014

Abstract

Background and Aims: Ovarian cancer treatment is often hindered by cisplatin resistance, frequently mediated by dysregulated apoptosis. This study investigates a novel combination therapy to overcome this resistance by targeting key apoptotic regulators. To evaluate the effects of Listeriolysin O (LLO), alone and in combination with Cis and CFZ, on the mRNA expression of the anti-apoptotic gene Bcl-2 and the pro-apoptotic gene Bax in cisplatin-sensitive (A2780S) and cisplatin-resistant (A2780CisR) ovarian cancer cell lines.
Methods: A2780S and A2780CisR cells were treated for 72 hours with LLO, Cis, CFZ, and their combinations (Cis/LLO, CFZ/LLO, Cis/CFZ/LLO). The relative mRNA expression levels of Bcl-2 and Bax were quantified using quantitative real-time PCR (qRT-PCR), with normalization to the GAPDH housekeeping gene.
Results: LLO monotherapy had a minimal impact on gene expression. In stark contrast, all combination regimens induced significant alterations in the Bcl-2/Bax axis. The triple-combination (Cis/CFZ/LLO) was the most potent, driving Bcl-2 expression down to 10% and 18% of control levels in A2780S and A2780CisR cells, respectively (P<0.01), while concurrently upregulating Bax expression nearly three-fold (2.94 in A2780S, 2.86 in A2780CisR; P<0.01). The two-drug combinations of Cis/LLO and CFZ/LLO also significantly suppressed Bcl-2 and elevated Bax compared to control and LLO-only groups (P<0.05). The overall treatment effect was statistically significant for both genes in both cell lines (p < 0.05).
Conclusion: The combination of LLO with cisplatin and carfilzomib promotes a profound pro-apoptotic gene expression profile in ovarian cancer cells by drastically downregulating Bcl-2 and upregulating Bax. This multi-mechanistic strategy, which concurrently targets DNA integrity, proteostasis, and plasma membrane integrity, effectively overcomes cisplatin resistance and represents a highly promising therapeutic approach for chemoresistant ovarian carcinoma.

Keywords

Listeriolysin O (LLO)

Bcl-2

Bax

Cisplatin

Ovarian cancer

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