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.