Increased sensitivity of a metastatic model of prostate cancer to a novel tetravalent platinum analog.

Abstract

BACKGROUND:

DACH-Ac-Pt [(1R,2R-diaminocyclohexane)-(trans-diacetato)-(dichloro)-platinum(IV)] is a novel cisplatin (CDDP) analog, and we have evaluated its potential activity in human prostate cancers.

METHODS:

Cytotoxic, biochemical pharmacologic, cell cycle, and Western blot evaluations were conducted with platinum agents to assess the role of p53 genotype and androgen-dependence status on cellular response.

RESULTS:

CDDP and DACH-Ac-Pt were equiactive against mutant p53 and androgen-independent DU-145 or PC-3 tumor cells. In wild-type p53 cells, CDDP was threefold more potent against androgen-dependent LNCaP than isogenic androgen-independent LNCaP-LN3 cells. However, the analog was equipotent in these two wild-type p53 tumor models. The greater potency of DACH-Ac-Pt than CDDP in wild-type p53 cells was not due to increased cellular drug uptake or increased adduct levels, but correlated with a lower tolerance to DNA damage. The analog also activated the p53-p21(WAF1/CIP1) signal transduction pathway more efficiently in LNCaP and LNCaP-LN3 cells, and this induced G(1)-phase cell-cycle arrest. CDDP, in contrast, activated this pathway efficiently in LNCaP cells only. In addition, and compared to CDDP, DACH-Ac-Pt was more effective in inducing Bax and increasing the Bax/Bcl-2 ratios in both the tumor models.

CONCLUSIONS:

DACH-Ac-Pt is highly effective against wild-type p53 LNCaP and its LN3 variant, and this activity is androgen-independent. The differential induction of p21(WAF1/CIP1) and increase in Bax/Bcl-2 ratios with CDDP and DACH-Ac-Pt in LNCaP-LN3 cells appear to be linked to the relative activity of the two agents against this model.

• Authors: Kalpana Mujoo, Masayuki Watanabe, Abdul R Khokhar, Zahid H Siddik
• Journal: The Prostate (Prostate) Vol. 62 Issue 1 Pg. 91-100 (Jan 01 2005) ISSN: 0270-4137 [Print] United States
• PMID: 15389812 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• (diaminocyclohexane)(diacetato)(dichloro)platinum
• Androgens
• Antineoplastic Agents
• BAX protein, human
• DNA Adducts
• Organoplatinum Compounds
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Cyclin D1
• Cisplatin

Topics

• Androgens (metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cisplatin (analogs & derivatives, pharmacology)
• Cyclin D1 (drug effects)
• DNA Adducts (drug effects)
• Genes, p53 (drug effects)
• Humans
• Male
• Neoplasm Metastasis
• Organoplatinum Compounds
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-bcl-2 (drug effects)
• Signal Transduction
• bcl-2-Associated X Protein