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Resistomycin Suppresses Prostate Cancer Cell Growth by Instigating Oxidative Stress, Mitochondrial Apoptosis, and
Abeer S Aloufi1, Ola A Habotta2, Mohamed S Abdelfattah3
1Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
Abstract:
Globally, prostate cancer is among the most threatening and leading causes of death in men. This study, therefore, aimed to search for an ideal antitumor strategy with high efficacy, low drug resistance, and no or few adverse effects. Resistomycin is a natural antibiotic derived from marine actinomycetes, and it possesses various biological activities. Prostate cancer cells (PC3) were treated with resistomycin (IC12.5: 0.65 or IC25: 1.3 µg/mL) or 5-fluorouracil (5-FU; IC25: 7 µg/mL) for 24 h. MTT assay and flow cytometry were utilized to assess cell viability and apoptosis. Oxidative stress, apoptotic-related markers, and cell cycle were also assessed. The results revealed that the IC50 of resistomycin and 5-FU on PC3 cells were 2.63 µg/mL and 14.44 µg/mL, respectively. Furthermore, treated cells with the high dose of resistomycin showed an increased number of apoptotic cells compared to those treated with the lower dose. Remarkable induction of reactive oxygen species generation and lactate dehydrogenase (LDH) leakage with high malondialdehyde (MDA), carbonyl protein (CP), and 8-hydroxyguanosine (8-OHdG) contents were observed in resistomycin-treated cells. In addition, marked declines in glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in PC3 cells subjected to resistomycin therapy were observed. Resistomycin triggered observable cell apoptosis by increasing Bax, caspase-3, and cytosolic cytochrome c levels and decreasing Bcl-2 levels. In addition, notable downregulation of proliferating cell nuclear antigen (PCNA) and cyclin D1 was observed in resistomycin-treated cancerous cells. According to this evaluation, the antitumor potential of resistomycin, in a concentration-dependent manner, in prostate cancer cells was achieved by triggering oxidative stress, mitochondrial apoptosis, and cell cycle arrest in cancer cells. In conclusion, our investigation suggests that resistomycin can be considered a starting point for developing new chemotherapeutic agents for human prostate cancer.
Insights
Resistomycin, a marine-derived antibiotic, shows promise as a prostate cancer treatment by inducing cell death and halting cell cycle progression. This natural compound offers a potential new avenue for chemotherapy with fewer side effects.
Area of Science:
- Marine natural products
- Cancer biology
- Drug discovery
Background:
- Prostate cancer is a leading cause of male mortality worldwide.
- Current treatments face challenges with efficacy, drug resistance, and adverse effects.
- Resistomycin, a marine actinomycete antibiotic, exhibits diverse biological activities.
Purpose of the Study:
- To evaluate resistomycin's potential as an antitumor agent against prostate cancer.
- To investigate its mechanism of action, including effects on cell viability, apoptosis, and cell cycle.
- To compare its efficacy with a standard chemotherapy drug, 5-fluorouracil (5-FU).
Main Methods:
- Prostate cancer (PC3) cells were treated with varying concentrations of resistomycin or 5-FU.
- Cell viability and apoptosis were assessed using MTT assay and flow cytometry.
- Oxidative stress markers, apoptotic markers, and cell cycle regulators were analyzed.
Main Results:
- Resistomycin demonstrated significant cytotoxicity against PC3 cells (IC50: 2.63 µg/mL) compared to 5-FU (IC50: 14.44 µg/mL).
- Resistomycin induced apoptosis, increased reactive oxygen species, and altered levels of key apoptotic and cell cycle proteins in a dose-dependent manner.
- The compound triggered oxidative stress and mitochondrial apoptosis pathways, leading to cell cycle arrest.
Conclusions:
- Resistomycin exhibits potent antitumor activity against prostate cancer cells.
- Its mechanism involves inducing oxidative stress, mitochondrial apoptosis, and cell cycle arrest.
- Resistomycin represents a promising lead compound for developing novel prostate cancer chemotherapeutics.
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