ABSTRACT
Combination therapy is often an effective strategy to treat cancer. In this study, we examined the growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/ß agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), or a DNA methyl transferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine, on androgen receptor (AR)-positive and AR-negative prostate cancer cell lines (LNCaP and PC-3, respectively). We found that the combination therapy of SAHA and Am80 showed an enhanced growth-inhibitory effect on LNCaP cells. Further studies with various HDAC isotype-selective inhibitors showed that SAHA and KD5170 (a selective class I and II HDAC inhibitor) each increased the RARα protein level in LNCaP cells. Our results indicate that the target of the enhancing effect belongs to the Class IIb HDACs, especially HDAC6. Dual targeting of Class IIb HDAC and RARα may be a candidate therapeutic strategy for prostate cancer.
Subject(s)
Benzoates/therapeutic use , Decitabine/pharmacology , Prostatic Neoplasms/drug therapy , Pyridines/pharmacology , Sulfonamides/pharmacology , Tetrahydronaphthalenes/therapeutic use , Vorinostat/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Benzoates/administration & dosage , Benzoates/pharmacokinetics , Cell Line, Tumor , Decitabine/administration & dosage , Drug Synergism , Drug Therapy, Combination , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/pharmacology , Humans , Male , Pyridines/administration & dosage , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/metabolism , Sulfonamides/administration & dosage , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/pharmacokinetics , Vorinostat/administration & dosageABSTRACT
Bisphosphonates have high affinity for hydroxyapatite (HA), which is abundantly present in bone. Also, platinum complexes are known that have a wide spectrum of antitumor activities. The conjugate of bisphosphonate and a platinum complex might have HA affinity and antitumor activity, and become a drug for metastatic bone tumor. In this study, the authors synthesized platinum complexes that had dialkyl bisphosphonic acid as a ligand, and evaluated the possibility of the synthesized complexes as a drug for metastatic bone tumor. The synthesized dialkyl bisphosphonate platinum(II) complex was characterized, and its stability in an aqueous solution was also confirmed. The synthesized platinum complex showed higher HA affinity than other platinum complexes such as cisplatin and carboplatin in an experiment of adsorption to HA. In vitro, the platinum complex showed tumor growth inhibitory effect stronger than or equal to cisplatin, which is the most commonly used antitumor agent. Moreover, the platinum complex showed a bone absorption inhibitory effect on the osteoclast. These results suggest potential of dialkyl bisphosphonate platinum(II) complexes as a drug for metastatic bone tumor.
