Prostate cancer remains a global health challenge, ranking as the second most commonly diagnosed cancer among men. Although treatments such as androgen deprivation therapy have been effective for early-stage prostate cancer, advanced stages such as castration-resistant prostate cancer present significant treatment challenges due to resistance to treatments. Current approaches targeting androgen receptor (AR) signaling, such as taxanes and newer agents, show limited success. Cisplatin, a widely used anticancer drug, has been used in combination therapies, but its use is limited by serious side effects, including renal toxicity, highlighting the need for safer and more effective treatment options.
In a recent study published in Volume 63, Issue 44 of the journal Inorganic Chemistry On September 11, 2024, a team of researchers led by Associate Professor Yoshihisa Hirota from Shibaura Institute of Technology (SIT) and Professor Seiji Komeda from Suzuka University of Medical Science, investigated the potential of dinuclear platinum(II) complexes with an azolate bridge ( azolato). -bridged complexes) in the treatment of prostate cancer. The study focused in particular on a complex called 5-HY ([{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)](ClO4)2) as an alternative to cisplatin. These complexes are characterized by their water solubility and promising antiproliferative effects against prostate cancer cell lines, with minimal toxicity compared to traditional platinum-based drugs.
“The first platinum-based drug, cisplatin, has a strong effect on cancer by binding nuclear DNA, but it also affects normal cells and can cause serious side effects. We had data showing that certain azolate-bridged complexes inhibit AR signaling, which is extremely important for prostate cancer proliferation, in addition to antitumor activity initiated by DNA binding. Therefore, this study was conducted to elucidate the mechanism of AR signaling inhibition by the azole-bridged complex, 5-HY..”, explains Dr. Hirota.
The team used a variety of methods to assess AR dynamics and therapeutic effects in LNCaP prostate cancer cells. They used azolato-bridged complexes, cisplatin and the AR antagonist KW-365 to investigate their efficacy and performed cell viability, gene expression and protein analyses. In addition, the team used immunofluorescence staining to visualize AR expression and assessed apoptosis (programmed cell death), cell cycle distribution and nuclear platinum accumulation.
The results showed that 5-HY exhibited significantly stronger cytotoxic effects than cisplatin, with a low half-maximal inhibitory concentration for dihydrotestosterone (DHT)-induced cell proliferation. In addition, 5-HY effectively suppressed the expression of AR-responsive genes, such as PSA and TMPRSS2and induced apoptosis in AR-overexpressing cells. Immunofluorescence analysis confirmed that 5-HY promoted chromatin fragmentation, a hallmark of apoptosis, with greater efficacy observed at higher concentrations.
Mechanistically, 5-HY was found to bind directly to AR and DNA through non-covalent and covalent interactions. This binding induced conformational changes in the AR, possibly disrupting its function. In addition, 5-HY arrested the cell cycle at G2/M and sub-G1 phases, leading to apoptosis, particularly in AR-overexpressing cells. This multimodal mechanism of action distinguished 5-HY from cisplatin, which primarily targets DNA.
Despite its high antiproliferative activity, however, 5-HY exhibited lower acute toxicity in vivo compared to other platinum complexes, making it a promising candidate for further development. “The azolate-bridged complexes used in this research are expected to play a key role in the development of new therapies for advanced prostate cancer. For patients whose cancer has become resistant to conventional therapies, these complexes have the potential to effectively inhibit cancer progression with a multifaceted attack while minimizing side effects. Our approach could thus expand the treatment options for prostate cancer and improve the patient’s quality of life.” concludes Dr. Hirota with enthusiasm.
Overall, the results suggest that dinuclear platinum(II) complexes. could provide a more targeted approach to treating prostate cancer, specifically by inhibiting AR-mediated cell growth and survival, paving the way for the development of new, more effective treatments for advanced prostate cancer.
Source:
Journal Reference:
Arai, T., et al. (2024). Azolato-bridged dinuclear platinum(II) complexes exhibit androgen receptor-mediated antiprostate cancer activity. Inorganic Chemistry. doi.org/10.1021/acs.inorgchem.4c01093.
