Dissociation of the effects of the antitumour ether lipid ET-18-OCH₃ on cytosolic calcium and on apoptosis

Abstract

1. We have compared the effects of 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH₃) on the cytosolic free calcium concentration ([Ca²⁺]_i) and on apoptosis in several normal and leukaemia cells, including human polymorphonuclear neutrophils (PMNs), U937 cells, and undifferentiated as well as dimethylsulphoxide-differentiated HL60 cells (uHL60 and dHL60, respectively).

2. ET-18-OCH₃ produced apoptosis, as evidenced by DNA degradation into oligonucleosome-size fragments, in U937 and uHL60 cells, but not in dHL60 cells or PMNs.

3. ET-18-OCH₃ induced an increase in [Ca²⁺]_i mediated through the platelet-activating factor (PAF) receptor in U937, dHL60 cells and PMNs, as shown by cross-desensitization experiments and by prevention of the [Ca²⁺]_i changes by the PAF antagonist WEB-2170. The EC₅₀ values for the increase in [Ca²⁺]_i induced by PAF and ET-18-OCH₃ were 5×10⁻¹¹ and 2.5×10⁻⁷ M, respectively. In uHL60 cells the effect of ET-18-OCH₃ on [Ca²⁺]_i was very small and was not affected by WEB-2170.

4. PAF did not produce apoptosis in any of the cell types tested. WEB-2170 did not prevent the apoptosis induced by ET-18-OCH₃.

5. The uptake of [³H]-ET-18-OCH₃ was much larger in U937 and uHL60 cells than in dHL60 cells and PMNs.

6. Our results indicate that the apoptotic effect of ET-18-OCH₃ is not related to the changes in [Ca²⁺]_i, effected by interaction with plasma membrane PAF receptors, but to other actions which are associated with the uptake of this drug into the cells.

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