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.
Lazenby
C M
CM
Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom.
Thompson
M G
MG
Hickman
J A
JA
D000634:Aminoquinolines / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D015479:Leukemia, Myelomonocytic, Acute / Q000378:metabolism*; D010742:Phospholipid Ethers / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D005663:Furans; D010742:Phospholipid Ethers; C055462:SRI 62-834; C035738:Quin2-acetoxymethyl ester; D002118:Calcium