Novel platinum complex exhibits potent antiproliferative effects with low toxicity in preclinical prostate cancer models

Prostate cancer remains a global health challenge, ranking as the second most commonly diagnosed cancer among men. Although treatments such as androgen deprivation therapy are effective for early-stage prostate cancer, resistance to treatment poses major therapeutic challenges in advanced stages, such as castration-resistant prostate cancer.

Current approaches targeting androgen receptor (AR) signaling, including taxanes and newer agents, have shown limited success. Cisplatin, a widely used anticancer drug, is used in combination therapy, but its use is limited by severe side effects such as nephrotoxicity, highlighting the need for safer and more effective treatment options. It is emphasized.

In a study published in Inorganic Chemistry on September 11, 2024, a research team led by Associate Professor Yoshihisa Hirota of Shibaura Institute of Technology (SIT) and Professor Seiji Yoneda of Suzuka University of Medical Science explores the possibility of azolate-bridged dinuclear bodies. I searched. Platinum(II) complexes (azolate bridged complexes) in the treatment of prostate cancer.

This research explores a complex called 5-HY (({cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolate-N2,N3))(ClO4)2) as an alternative to cisplatin. Particularly focused. These complexes are characterized by water solubility and promising antiproliferative effects against prostate cancer cell lines, with minimal toxicity compared to conventional platinum-based drugs.

“Cisplatin, the first platinum-based drug, has powerful effects on cancer by binding to nuclear DNA, but it also affects normal cells and can cause serious side effects. is that some azolate crosslinked complexes are AR We obtained data showing that inhibition of signal transduction by azolate cross-linking is critical for prostate cancer growth, in addition to its anticancer effects initiated by DNA binding. This was done to elucidate the mechanism of inhibition of AR signaling complex, 5-HY,” explains Dr. Hirota.

The research team used a variety of methods to assess AR dynamics and treatment efficacy in LNCaP prostate cancer cells. They utilized the azolate cross-linked complex, cisplatin, and the AR antagonist KW-365 to investigate their efficacy and performed cell viability, gene expression, and protein analyses.

Additionally, the team used immunofluorescence staining to visualize AR expression and assess apoptosis (programmed cell death), cell cycle distribution, and intranuclear platinum accumulation.

The results showed that 5-HY exhibited significantly more potent cytotoxic effects than cisplatin, with a lower half-maximal inhibitory concentration on dihydrotestosterone (DHT)-induced cell proliferation.

Furthermore, 5-HY effectively suppressed the expression of AR-responsive genes such as PSA and TMPRSS2 and induced apoptosis in AR-overexpressing cells. Immunofluorescence analysis confirmed that 5-HY promotes chromatin fragmentation, a hallmark of apoptosis, with higher effects observed at higher concentrations.

Mechanistically, 5-HY was found to bind directly to AR and DNA through both noncovalent and covalent interactions. This binding may cause structural changes in AR and destroy its function. Furthermore, 5-HY arrests the cell cycle in G2/M and sub-G1 phases and causes apoptosis, especially in cells overexpressing AR. This multimodal mechanism of action distinguishes 5-HY from cisplatin, which primarily targets DNA.

However, despite its high antiproliferative activity, 5-HY has been shown to have low acute toxicity in vivo compared to other platinum complexes, making it a promising candidate for further development.

“The azolate cross-linked conjugate used in this study is expected to play an important role in the development of new treatments for advanced prostate cancer. For patients, these complexes have the potential to effectively inhibit cancer progression with multiple treatments.”Thus, a multilayered attack with minimal side effects can help combat prostate cancer. “This could expand treatment options and improve patients’ quality of life,” concluded Dr. Hirota.

Overall, this result suggests that dinuclear platinum(II) complexes may provide a more targeted approach to the treatment of prostate cancer, particularly by inhibiting AR-mediated cell proliferation and survival, leading to progression of disease progression. This finding may pave the way for the development of new and more effective treatments for prostate cancer. .