Prostate cancer is one of the most prevalent and deadly forms of cancer in men worldwide. While treatments like androgen deprivation therapy and chemotherapy with drugs like cisplatin can be effective, many patients develop resistance over time, leading to a poor prognosis. However, a groundbreaking new study has uncovered a promising approach to enhance the effectiveness of cisplatin-based chemotherapy for prostate cancer.
The research, led by a team of scientists from Guizhou Institute of Technology and Guizhou University, focused on inhibiting a critical DNA repair enzyme called Bloom helicase (BLM). BLM plays a crucial role in the homologous recombination (HR) DNA repair pathway, which can help cancer cells survive the DNA damage caused by chemotherapeutic agents like cisplatin. By targeting BLM, the researchers aimed to sensitize prostate cancer cells to the DNA-damaging effects of cisplatin.
The researchers used a novel BLM inhibitor called AO/854, which they had previously developed and shown to suppress tumor growth and metastasis in prostate cancer cells. In this study, they demonstrated that AO/854 could significantly enhance the anticancer effects of cisplatin, both in vitro and in a mouse xenograft model of prostate cancer.
cycle’>cell cycle arrest induced by cisplatin, leading to more severe DNA damage and cell death.
These findings suggest that targeting the BLM helicase with AO/854 could be a promising strategy to improve the efficacy of cisplatin-based chemotherapy for prostate cancer, particularly in cases where the cancer has become resistant to standard treatments. The combination of a BLM inhibitor and a DNA-damaging agent like cisplatin may represent a novel and effective approach to tackling this challenging disease.
Prostate Cancer: A Persistent Challenge
Prostate cancer is the second most common cancer in men globally and the fifth leading cause of cancer-related deaths in men. In the United States alone, it is estimated that prostate cancer will account for 27% of all new cancer cases in men in 2022, making it the most frequently diagnosed cancer in the country. While various treatment options, including prostatecancer’>castration-resistant prostate cancer (CRPC), which is associated with a poor prognosis.
The Role of DNA Repair in Prostate Cancer
One of the key factors contributing to the development of CRPC is the ability of cancer cells to evade and overcome the DNA-damaging effects of chemotherapeutic agents, such as cisplatin. Cancer cells can activate various DNA repair pathways, including the Click Here
</a> pathway, to counteract the DNA damage induced by these drugs.</p>
<p>The Bloom helicase (BLM) protein plays a crucial role in the HR pathway, as it helps to unwind and process DNA during the repair process. By inhibiting BLM, the researchers aimed to disrupt the cancer cells’ ability to effectively repair the DNA damage caused by cisplatin, thereby enhancing the drug’s anticancer effects.</p>
<p><h3>Synergistic Effects of AO/854 and Cisplatin</h3>
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<p>The researchers first demonstrated that the levels of BLM in prostate cancer cells were inversely correlated with their sensitivity to cisplatin. Cells with higher BLM expression were more resistant to the drug, while cells with lower BLM levels were more sensitive.</p>
<p><figure class="wp-block-image size-large"><img decoding="async" src="https://famefreq.s3.us-east-2.amazonaws.com/1729767789_41598_2024_75938_Fig1_HTML.png" alt="figure 1" class="wp-image-1" /><figcaption class="wp-element-caption">Fig. 1</figcaption></figure>
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<p>Next, the team evaluated the combined effects of the novel BLM inhibitor AO/854 and cisplatin on prostate cancer cell lines. They found that the combination of these two agents significantly enhanced the inhibition of cell proliferation, migration, and invasion compared to either treatment alone.</p>
<p>Using a mathematical model called the Chou-Talalay method, the researchers determined that AO/854 and cisplatin had a synergistic effect on prostate cancer cells, meaning that the combination was more effective than the sum of the individual treatments.</p>
<p><h3>Increased DNA Damage and Apoptosis</h3>
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<p>The researchers then investigated the underlying mechanisms behind the synergistic effects of AO/854 and cisplatin. They found that the combination treatment led to a greater increase in DNA double-strand breaks (DSBs), as evidenced by the elevated levels of the DNA damage marker γH2AX.</p>
<p><figure class="wp-block-image size-large"><img decoding="async" src="https://famefreq.s3.us-east-2.amazonaws.com/1729767791_41598_2024_75938_Fig2_HTML.png" alt="figure 2" class="wp-image-2" /><figcaption class="wp-element-caption">Fig. 2</figcaption></figure>
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<p>Furthermore, the combination of AO/854 and cisplatin induced a more significant cell cycle arrest in the G2/M phase, indicating that the cancer cells were unable to properly progress through the cell cycle and repair the DNA damage. This, in turn, led to a dramatic increase in apoptosis, or programmed cell death, in the prostate cancer cells.</p>
<p><h3>Enhanced Antitumor Efficacy in Vivo</h3>
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<p>To validate their findings in a more clinically relevant setting, the researchers conducted experiments using a mouse xenograft model of prostate cancer. They found that the combination of AO/854 and cisplatin significantly suppressed tumor growth compared to either treatment alone.</p>
<p><figure class="wp-block-image size-large"><img decoding="async" src="https://famefreq.s3.us-east-2.amazonaws.com/1729767793_41598_2024_75938_Fig3_HTML.png" alt="" class="wp-image-3" /><figcaption class="wp-element-caption">Table 1 The CI values of AO/854 and CDDP in PC3, 22RV1 and LNCap cells.</figcaption></figure>
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<p>The researchers also observed higher levels of the DNA damage marker γH2AX in the tumors treated with the combination therapy, further confirming the ability of AO/854 to enhance the DNA-damaging effects of cisplatin.</p>
<p><h3>Implications and Future Directions</h3>
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<p>The results of this study suggest that targeting the BLM helicase with a novel inhibitor like AO/854 could be a promising strategy to improve the effectiveness of cisplatin-based chemotherapy for prostate cancer. By sensitizing cancer cells to the DNA-damaging effects of cisplatin, the combination therapy may be able to overcome the resistance that often develops during standard treatment.</p>
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<p>Moreover, the use of a BLM inhibitor in combination with a lower dose of cisplatin could potentially reduce the severe side effects associated with high-dose cisplatin therapy, such as nephrotoxicity. This approach could lead to a more effective and better-tolerated treatment option for patients with advanced or resistant prostate cancer.</p>
<p>Future research should focus on further validating the efficacy and safety of the AO/854 and cisplatin combination in additional preclinical models and, ultimately, in clinical trials. Investigating the potential of this strategy in other cancer types with DNA repair deficiencies, such as ovarian or pancreatic cancer, may also be a fruitful avenue of exploration.</p>
<p>Overall, this study represents an important step forward in the development of more effective and targeted therapies for prostate cancer, a disease that continues to pose a significant challenge to the medical community.</p>
<p>Author credit: This article is based on research by Xiaoyan Ma, Fu Tian, Yuanpin Xiao, Mengqiu Huang, Dandan Song, Xinlin Chen, Houqiang Xu.</p>
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