Prostate cancer, particularly in its advanced form, like castration-resistant prostate cancer, poses significant treatment difficulties. Traditional methods that focus on androgen receptor (AR) signaling often fall short. A recent study examined the effectiveness of azolato-bridged dinuclear platinum(II) complexes, especially one called 5-H-Y, as potential alternatives. The researchers found that this complex can inhibit AR signaling and lead to cell death in prostate cancer cells, opening new possibilities for treatment.
Worldwide, prostate cancer is a major health concern, being the second most commonly diagnosed cancer among males. While androgen deprivation therapy is beneficial for early-stage prostate cancer, advanced stages such as castration-resistant prostate cancer present considerable challenges due to therapy resistance. Current therapies targeting androgen receptor (AR) signaling struggle with limited effectiveness. Cisplatin, commonly used in cancer treatment, is often combined with other drugs, but its significant side effects, including kidney damage, show the urgent need for safer and more effective alternatives.
In a study published on September 11, 2024, in Volume 63, Issue 44 of Inorganic Chemistry, researchers led by Associate Professor Yoshihisa Hirota from Shibaura Institute of Technology (SIT) and Professor Seiji Komeda of Suzuka University of Medical Science investigated azolato-bridged dinuclear platinum(II) complexes as a treatment for prostate cancer. The focus was specifically on a complex known as 5-H-Y ([{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)](ClO4)2), which offers water solubility and exhibits significant anticancer effects on prostate cell lines with lower toxicity than traditional platinum drugs.
According to Dr. Hirota, “Cisplatin, the first platinum-based drug, effectively targets cancer by binding to nuclear DNA, but it also affects normal cells, causing severe side effects. Previous data indicated some azolato-bridged complexes can inhibit AR signaling, crucial for prostate cancer growth, along with the anticancer effects triggered by DNA binding. Hence, this study aimed to elucidate how the azolato-bridged complex 5-H-Y inhibits AR signaling.”
The research team employed multiple techniques to assess AR dynamics and the therapeutic potential in LNCaP prostate cancer cells. They examined the effects of azolato-bridged complexes, cisplatin, and the AR inhibitor KW-365, conducting analyses on cell viability, gene expression, and protein levels. They also used immunofluorescence staining to observe AR expression and to measure apoptosis (programmed cell death), cell cycle phases, and accumulation of nuclear platinum.
The findings revealed that 5-H-Y had a significantly stronger cytotoxic impact than cisplatin, exhibiting a low half-maximal inhibitory concentration against DHT-induced cell growth. Furthermore, 5-H-Y substantially reduced the expression of AR-regulated genes like PSA and TMPRSS2 while triggering apoptosis in cells with high AR levels. Immunofluorescence results demonstrated that 5-H-Y induced chromatin fragmentation, a sign of apoptosis, particularly at higher concentrations.
Mechanistically, 5-H-Y was shown to attach directly to AR and DNA through noncovalent and covalent means. This interaction caused conformational changes in AR, likely disrupting its function. Additionally, 5-H-Y hindered the cell cycle at the G2/M and sub-G1 phases, intensifying apoptosis, especially in cells that overexpress AR. This multi-faceted action set 5-H-Y apart from cisplatin, which focuses mainly on DNA.
Though 5-H-Y showed strong antiproliferative activity, it exhibited reduced acute toxicity in living organisms compared to other platinum complexes, making it an appealing candidate for future study. Dr. Hirota remarked, “The azolato-bridged complexes from this research are promising for developing new interventions for advanced prostate cancer. For patients whose cancer has resisted standard therapies, these complexes could effectively slow down cancer progression with less severe side effects. Our findings aim to expand treatment options and enhance the quality of life for patients with prostate cancer.”
In summary, the study suggests that dinuclear platinum(II) complexes could offer a more focused method for treating prostate cancer, specifically by inhibiting AR-driven cell growth and survival, thus paving the way for new and effective therapies for advanced prostate cancer.
