Increased intracellular cAMP renders HL-60 cells resistant to cytotoxicityof taxol

The treatment of advanced cancers with paclitaxel (taxol) is hindered by th e development of drug resistance. Resistance to taxol is known to be associ ated with multidrug resistance (MDR) and a mutation affecting either the al pha- or beta-subunit of tubulin. In this study, we demonstrated that an int racellular cAMP level may also play an important role in resistance to taxo l in HL-60, acute promyelocytic leukemia cells. Exposure of HL-60 cells to various doses of taxol for 18 hr resulted in cell death. However, pretreatm ent of the cells with cAMP analogs such as N-6 : O-2-dibutyl CAMP (Db-cAMP) , 8-(4-chlorophenylthio) cAMP (CPT-cAMP) and 8-bromo-cAMP (8-Br-cAMP) or an intracellular cAMP elevating agent such as forskolin apparently rendered H L-60 cells more resistant to taxol, but not with dimethyl sulfoxide (DMSO) or retinoic acid (RA), well known differentiating agents. To investigate wh ether protein kinase A (PKA) activated by an increase in intracellular cAMP level could be involved in increased taxol resistance of the cells, we exa mined the effects of PKA inhibitors, including H-89 and KT5720, on taxol re sistance induced by Db-cAMP. The PKA inhibitors significantly abolished Db- cAMP-induced taxol resistance. These results suggest that cAMP analogs may render tumor cells more resistant to taxol via PKA activation.