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.