8-Chloroadenosine 3',5'-monophosphate as a novel modulator of multidrug resistance

Multidrug resistance (MDR) is a major obstacle in the chemotherapy of cancer, 8-chloroadenosine 3',5'-monophosphate (8-Cl-cAMP), a site-selective analog of cAMP, produced a potent growth inhibition in a spectrum of MDR cell lines. The IC₅₀ (concentration inhibiting 50% of cell proliferation) of 8- Cl-cAMP at 6 days ranged from 0.1 to 3.0 μM in both P-glycoprotein (pgp)- associated and pgp-unassociated MDR cells, and the growth inhibition occurred with continued cell viability. Growth inhibition paralleled down-regulation of RIα subunit and catalytic activity of cAMP-dependent protein kinase. 8- Cl-cAMP also provoked the suppression of the promoter activity of the MDR1 gene. These results demonstrate that type I cAMP-dependent protein kinase plays a role in drug resistance and that 8-Cl-cAMP is a novel modulator of multidrug resistance.