Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells.

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.

EML4-ALK rearrangement in squamous cell carcinoma shows significant response to anti-ALK inhibitor drugs crizotinib and alectinib.

EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history.

Antidepressants and platinum drugs.

BACKGROUND/AIM: Antidepressants are frequently prescribed concurrently with anti-cancer drugs and may have synergistic, additive or antagonistic effects. The present work investigated the effect of antidepressants on the cytotoxicity of platinum agents cisplatin, carboplatin and oxaliplatin. MATERIALS AND METHODS: The cytotoxicity of platinum drugs alone or in combination with antidepressants was measured in HCT116 wild-type (wt), HCT116 (p53 -/-), HT-29, SKOV3 and A2780 cells using an apoptosis-based assay. RESULTS: The effect of antidepressants on platinum cytotoxicity is both cell type- and drug dependent. Mostly additive effects were observed. Desipramine and fluoxetine caused the greatest effects, with cisplatin in general being most sensitive to their presence. There is little effect of p53 status on the drug-drug interaction while the calmodulin inhibitor W7 augmented cisplatin cytotoxicity relative to carboplatin and oxaliplatin. CONCLUSION: The drug-drug interaction between antidepressants and platinum anti-cancer agents requires detailed evaluation for optimization of patient care.

A new approach to glycan targeting: enzyme inhibition by oligosaccharide metalloshielding.

Metalloglycomics - the effects of defined coordination compounds on oligosaccharides and their structure and function - opens new areas for bioinorganic chemistry and expands its systematic study to the third major class of biomolecules after DNA/RNA and proteins.