Pharmacologic circumvention of multidrug resistance

Ford, James M.; Hait, William N.

doi:10.1007/978-94-011-0826-3_9

Cited by 42 publications

(54 citation statements)

References 212 publications

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“…The affinity of CBP501 to CaM shown by SPR analysis is 10-fold higher than that of CBP501 to 14-3-3z. In contrast, KN93, an inhibitor of CaMKII, and ML-7, an inhibitor of MLCK, had no synergistic effect with cisplatin (data not shown), Although we have no clear answer for how CaM inhibition leads to increased platinum levels in cells, a multidrug resistant efflux transporter, multidrug resistance 1, was suggested to be regulated by CaM (25,26). In addition, SK4 (small conductance calciumactivated potassium channel 4), a calcium-dependent potassium ion channel, is activated by CaM and has been shown to participate in platinum uptake (27).…”

Section: Discussionmentioning

confidence: 88%

CBP501-Calmodulin Binding Contributes to Sensitizing Tumor Cells to Cisplatin and Bleomycin

Mine

Yamamoto

Saito

et al. 2011

Molecular Cancer Therapeutics

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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 2þ . 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 ¼ 4.62 Â 10 À8 mol/L) that is reversed by Ca 2þ , whereas the K d for the complex between CBP501 and 14-3-3 is approximately 10-fold weaker and is Ca 2þ independent. We conclude that CaM inhibition contributes to CBP501 0 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.

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Section: Discussionmentioning

confidence: 88%

CBP501-Calmodulin Binding Contributes to Sensitizing Tumor Cells to Cisplatin and Bleomycin

Mine

Yamamoto

Saito

et al. 2011

Molecular Cancer Therapeutics

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“…In addition, some of the chemicals in the mixture might be direct inhibitors of the transporter activity. The resultant competition or inhibition, termed chemosensitization, can decrease transporter activity such that toxic substances normally excluded from the cell can now enter (4,5). We will discuss how these weak links can have subtle but detrimental consequences.…”

Section: Protecting Cells Against Toxicantsmentioning

confidence: 99%

Efflux Transporters: Newly Appreciated Roles in Protection against Pollutants

Epel¹,

Luckenbach²,

Stevenson³

et al. 2008

Environ. Sci. Technol.

158

112

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“…As Pgp is a broadspectrum efflux pump that binds a wide variety of hydrophobic compounds, it was relatively easy to identify potent inhibitors. However, attempts to characterize a pharmacophore so as to rationally develop better inhibitors have met with only modest success (Ford and Hait, 1990). Numerous clinical trials were conducted encouraged by studies demonstrating frequent expression of Pgp in various tumors, and supported by reports documenting the adverse prognostic impact of Pgp expression.…”

Section: Overcoming Drug Resistance Mediated By Abc Transportersmentioning

confidence: 99%

“…Numerous clinical trials were conducted encouraged by studies demonstrating frequent expression of Pgp in various tumors, and supported by reports documenting the adverse prognostic impact of Pgp expression. Agents evaluated since the early 1980s when these studies began include: verapamil, the phenothiazines, quinidine, quinacrine, quinine, amiodarone, several neuroleptics, tamoxifen, progesterone, cyclosporin A, dexverapamil, dexniguldipine, GF120918, PSC-833 (valspodar), VX-710 (biricodar), XR9576 (tariquidar) and others (Ford and Hait, 1990;Trump et al, 1992;Fisher et al, 1996). Trials attempting to modulate drug resistance have undergone a gradual evolution from early trials using agents already approved by the FDA for other indications, to subsequent studies with more potent agents developed as Pgp inhibitors, to ongoing trials using highly potent and specific inhibitors.…”

Section: Overcoming Drug Resistance Mediated By Abc Transportersmentioning

confidence: 99%