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Published on: April 5, 2018
Phenotypic discovery of a pyrimidine derivative with dual anti-prostate cancer and cardioprotective potential via ROS
Yaquan Cao1, Yaxi Wu2, Yunfei Li1
1College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan 471003, PR China.
Abstract:
Cardiotoxicity remains a major limitation of current anticancer therapies, highlighting the need for agents that combine antitumor efficacy with intrinsic cardiac safety. Phenotypic screening of a pyrimidine-based compound library identified compound 9v as a potent anti-prostate cancer candidate with dual biological functions. Compound 9v inhibited PC-3 cell proliferation with an IC₅₀ of 3.96 ± 0.18 μM, outperforming 5-fluorouracil, and markedly suppressed colony formation and migration while inducing apoptosis. Mechanistic studies showed that 9v activated the mitochondrial apoptotic pathway by increasing Bax, cleaved caspase-9, and cleaved caspase-3 levels while reducing Bcl-2 expression. Remarkably, 9v exerted bidirectional regulation of ROS homeostasis, promoting ROS accumulation in PC-3 cells but suppressing oxidative stress in H9C2 cardiomyocytes under H₂O₂ challenge. In addition, 9v exhibited weak cytotoxicity toward normal prostate stromal cells, no obvious acute toxicity in mice, and no detectable cardiotoxicity in vitro. Moreover, it exhibited protective effects against oxidative injury in cardiomyocytes, as demonstrated by increased cell viability and decreased LDH and cTnT release. Taken together, these results identify 9v as a promising lead compound with both anti-prostate cancer activity and cardioprotective potential in an in vitro oxidative stress model, providing a basis for the development of multifunctional anticancer agents with improved cardiovascular safety.
Insights
A novel compound, 9v, shows potent anti-prostate cancer effects by inducing apoptosis. Remarkably, it also protects heart cells from oxidative stress, offering a promising dual-action therapeutic strategy.
Area of Science:
- Oncology
- Cardiology
- Medicinal Chemistry
Background:
- Cardiotoxicity is a significant challenge in cancer therapy, necessitating the development of safer, effective agents.
- Current treatments often compromise cardiac function, driving the search for compounds with dual antitumor and cardioprotective properties.
Purpose of the Study:
- To identify and characterize a novel pyrimidine-based compound with potent anti-prostate cancer activity and intrinsic cardiac safety.
- To investigate the mechanisms underlying the compound's efficacy and cardioprotective effects.
Main Methods:
- Phenotypic screening of a pyrimidine-based library to identify anti-prostate cancer candidates.
- In vitro assays to assess cytotoxicity, proliferation inhibition, apoptosis induction, and migration suppression in cancer cells.
- Mechanistic studies involving Western blotting to analyze apoptotic pathway markers and reactive oxygen species (ROS) homeostasis.
- In vitro cardiotoxicity and cardioprotection assays using H9C2 cardiomyocytes under oxidative stress.
Main Results:
- Compound 9v demonstrated potent inhibition of PC-3 prostate cancer cell proliferation (IC₅₀ = 3.96 μM), surpassing 5-fluorouracil, and suppressed colony formation, migration, and induced apoptosis.
- Mechanistically, 9v activated the mitochondrial apoptotic pathway (Bax, cleaved caspase-9, cleaved caspase-3) and modulated ROS homeostasis, inducing ROS in cancer cells while suppressing it in cardiomyocytes.
- Compound 9v exhibited low cytotoxicity to normal cells, no acute toxicity in vivo, and importantly, demonstrated significant cardioprotective effects against oxidative injury in vitro.
Conclusions:
- Compound 9v is a promising lead candidate with dual anti-prostate cancer efficacy and cardioprotective potential.
- Its ability to selectively modulate ROS and activate apoptosis pathways offers a novel therapeutic strategy for prostate cancer with improved cardiovascular safety.
- Further development of 9v could lead to multifunctional anticancer agents with enhanced patient safety profiles.
