title: CBP501-calmodulin binding contributes to sensitizing tumor cells to cisplatin and bleomycin.
abstract: CBP501 is an anticancer drug currently in randomized phase II clinical trials for patients with non-small cell lung cancer and malignant pleural mesothelioma. CBP501 was originally described as a unique G(2) checkpoint-directed agent that binds to 14-3-3, inhibiting the actions of Chk1, Chk2, mitogen-activated protein kinase-activated protein kinase 2, and C-Tak1. However, unlike a G(2) checkpoint inhibitor, CBP501 clearly enhances the accumulation of tumor cells at G(2)-M phase that is induced by cisplatin or bleomycin at low doses and short exposure. By contrast, CBP501 does not similarly affect the accumulation of tumor cells at G(2)-M that is induced by radiation, doxorubicin, or 5-fluorouracil treatment. Our recent findings point to an additional mechanism of action for CBP501. The enhanced accumulation of tumor cells at G(2)-M upon combined treatment with cisplatin and CBP501 results from an increase in intracellular platinum concentrations, which leads to increased binding of platinum to DNA. The observed CBP501-enhanced platinum accumulation is negated in the presence of excess Ca(2+). Some calmodulin inhibitors behave similarly to, although less potently than, CBP501. Furthermore, analysis by surface plasmon resonance reveals a direct, high-affinity molecular interaction between CBP501 and CaM (K(d) = 4.62 × 10(-8) mol/L) that is reversed by Ca(2+), whereas the K(d) for the complex between CBP501 and 14-3-3 is approximately 10-fold weaker and is Ca(2+) independent. We conclude that CaM inhibition contributes to CBP501's activity in sensitizing cancer cells to cisplatin or bleomycin. This article presents an additional mechanism of action which might explain the clinical activity of the CBP501-cisplatin combination.
authors.affiliation: CanBas Co., Ltd., 2-2-1 Otemachi, Numazu City 410-0801, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mine
authors.forename: Sayaka
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Saito
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Chikako
authors.initials: C
authors.lastname: Suda
authors.forename: Machiyo
authors.initials: M
authors.lastname: Ishigaki
authors.forename: Donald W
authors.initials: DW
authors.lastname: Kufe
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawabe
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001761:Bleomycin / Q000008:administration & dosage / Q000494:pharmacology*; D002122:Calcium Chloride / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018736:DNA Adducts / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D002147:Calmodulin; C517976:Cdc25C phosphatase (211-221); D018736:DNA Adducts; D010446:Peptide Fragments; C057270:cisplatin-DNA adduct; D001761:Bleomycin; D020687:cdc25 Phosphatases; D002122:Calcium Chloride; D002945:Cisplatin