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The Induction of G2/M Phase Cell Cycle Arrest and Apoptosis by the Chalcone Derivative 1C in Sensitive and Resistant
Šimon Salanci1, Mária Vilková2, Lola Martinez3
1Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia.
Abstract:
Ovarian cancer ranks among the most severe forms of cancer affecting the female reproductive organs, posing a significant clinical challenge primarily due to the development of resistance to conventional therapies. This study investigated the effects of the chalcone derivative 1C on sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines. Our findings revealed that 1C suppressed cell viability, induced cell cycle arrest at the G2/M phase, and triggered apoptosis in both cell lines. These effects are closely associated with generating reactive oxygen species (ROS). Mechanistically, 1C induced DNA damage, modulated the activity of p21, PCNA, and phosphorylation of Rb and Bad proteins, as well as cleaved PARP. Moreover, it modulated Akt, Erk1/2, and NF-κB signaling pathways. Interestingly, we observed differential effects of 1C on Nrf2 levels between sensitive and resistant cells. While 1C increased Nrf2 levels in sensitive cells after 12 h and decreased them after 48 h, the opposite effect was observed in resistant cells. Notably, most of these effects were suppressed by the potent antioxidant N-acetylcysteine (NAC), underscoring the crucial role of ROS in 1C-induced antiproliferative activity. Moreover, we suggest that modulation of Nrf2 levels can, at least partially, contribute to the antiproliferative effect of chalcone 1C.
Insights
The chalcone derivative 1C combats ovarian cancer by reducing cell viability and inducing apoptosis, with effects linked to reactive oxygen species (ROS). This compound shows promise against both sensitive and resistant cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ovarian cancer presents a significant therapeutic challenge due to treatment resistance.
- Chalcone derivatives are being explored for their potential anticancer properties.
Purpose of the Study:
- To investigate the antiproliferative effects of chalcone derivative 1C on sensitive and cisplatin-resistant ovarian cancer cell lines.
- To elucidate the mechanisms underlying 1C's action, including its role in reactive oxygen species (ROS) generation and signaling pathway modulation.
Main Methods:
- Utilized sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines.
- Assessed cell viability, cell cycle progression, apoptosis, ROS production, DNA damage, protein expression/phosphorylation, and signaling pathway activation.
- Investigated the role of ROS using the antioxidant N-acetylcysteine (NAC).
Main Results:
- Chalcone 1C suppressed cell viability, induced G2/M cell cycle arrest, and promoted apoptosis in both ovarian cancer cell lines.
- 1C-induced effects were associated with increased ROS generation, DNA damage, and modulation of key proteins (p21, PCNA, Rb, Bad, PARP) and signaling pathways (Akt, Erk1/2, NF-κB).
- Differential modulation of Nrf2 levels was observed in sensitive versus resistant cells, and ROS-dependent effects were confirmed by NAC treatment.
Conclusions:
- Chalcone 1C exhibits significant antiproliferative and pro-apoptotic activity against ovarian cancer cells, irrespective of cisplatin resistance.
- ROS generation is a critical mediator of 1C's anticancer effects.
- Nrf2 modulation may contribute to the observed antiproliferative activity, suggesting potential therapeutic strategies for ovarian cancer.
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