title: Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells.
abstract: A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic antidepressant desipramine. Desipramine is used for treating neuropathic pain, particularly in prostate cancer patients. The clinically used drugs cisplatin (cis-[PtCl(2)(NH(3))(2)]), oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum(II)], and the cationic trinuclear agent BBR3464 [{trans-PtCl(NH(3))(2)}(2)-μ-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+), which has undergone evaluation in phase II clinical trials for activity in lung and ovarian cancers, were evaluated. Surprisingly, desipramine greatly augments the cytotoxicity of all the platinum-based chemotherapeutics in HCT116 colorectal carcinoma cell lines. Desipramine enhanced cellular accumulation of cisplatin, but had no effect on the accumulation of oxaliplatin or BBR3464, suggesting that enhanced accumulation could not be a consistent means by which desipramine altered the platinum-drug-mediated cytotoxicity. The desipramine/cisplatin combination resulted in increased levels of p53 as well as mitochondrial damage, caspase activation, and poly(ADP ribose) polymerase cleavage, suggesting that desipramine may synergize with cisplatin more than with other platinum chemotherapeutics partly by activating distinct apoptotic pathways. The study argues that desipramine may be a means of enhancing chemoresponsiveness of platinum drugs and the results warrant further investigation. The results emphasize the importance of understanding the differential pharmacological action of adjuvants employed in combinations with cancer chemotherapeutics.
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, 1001 W. Main St., Richmond, VA 23284, USA.
authors.forename: Peyman
authors.initials: P
authors.lastname: Kabolizadeh
authors.forename: Brigitte J
authors.initials: BJ
authors.lastname: Engelmann
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pullen
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Stewart
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
mesh_terms: D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D003891:Desipramine / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry* / Q000494:pharmacology; D012709:Serum Albumin / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000928:Antidepressive Agents; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D012709:Serum Albumin; D010984:Platinum; D004247:DNA; D003891:Desipramine