Elevation of leukemic cell intracellular calcium by the ether lipid SRI 62-834

SRI 62-834 is a novel antineoplastic ether lipid which is currently undergoing a Phase 1 clinical trial in the United Kingdom. Its mechanism of action has not been defined. Incubation of 7.5 X 10(6)/ml HL-60 human myelomonocytic leukemia cells with between 10 and 50 microM SRI 62-834 brought about a concentration-dependent, biphasic rise in intracellular calcium, as measured by the calcium-sensitive fluorescent dye Quin-2 AM. Incubation with 30 microM SRI 62-834 elevated intracellular calcium from 110 to 415 nM after 10 min in a typical experiment; this concentration inhibited cell growth by greater than 90% (50% inhibition of growth was observed at 8 microM). The calcium channel blockers verapamil and prenylamine did not inhibit the SRI 62-834-induced elevation of intracellular calcium. Incubation of SRI 62-834 with K562 erythroblastic leukemia cells also brought about a rise in the intracellular calcium. The growth of K562 cells was less sensitive to SRI 62-834 (dose to produce 50% growth inhibition, 65 microM) compared to HL-60 cells, and significant intracellular calcium rises, which were monophasic, required greater than 40 microM SRI 62-834. At a concentration of SRI 62-834 which inhibited both HL-60 and K562 growth by 90% (30 and 140 microM, respectively) an equivalent rise in intracellular calcium was observed (circa 400 nM). Preincubation of HL-60 or K562 cells with 1 to 100 nM 12-O-tetradecanoylphorbol-13-acetate for 10 min prior to the addition of SRI 62-834 inhibited the rise in intracellular calcium in a concentration-dependent manner. It is suggested that SRI 62-834-induced changes in intracellular calcium may contribute to its cytotoxicity and that the rise is not due to an early and grossly disruptive effect of the agent on membrane structure.