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ZY Dong, NE Ward, D Fan, KP Gupta and CA O'Brian
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
We investigated the effects that phorbol ester and diacylglycerol protein kinase C (PKC) activators had on the chemosensitivity of the human colon cancer cell line KM12L4a to Adriamycin (ADR), vincristine (VCR), and vinblastine (VLB) and on the intracellular accumulation of those drugs. Exposure of the cells to the PKC activator phorbol-12,13- dibutyrate (PDBu) (15 nM) during a 96-hr in vitro chemosensitivity assay significantly reduced the sensitivity of KM12L4a cells to ADR, VCR, and VLB, but not to 5-fluorouracil. Because a 96-hr treatment with 15 nM PDBu did not down-regulate PKC activity in KM12L4a cells, activation of PKC appeared to be responsible for the observed protection conferred by PDBu. PDBu-induced alterations in drug accumulation may account for its protective effects against these cytotoxic drugs, because both PDBu and the phorbol ester 12-O- tetradecanoyl-phorbol-13-acetate significantly reduced accumulation of [3H] VCR and [14C]ADR in the cultured human colon cancer cells. Unsaturated diacylglycerols are structural and functional analogues of phorbol ester PKC activators that are present in the lumen of the colon. We found that treatment of KM12L4a human colon cancer cells with the diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol (OAG) significantly reduced [14C]ADR and [3H]VCR accumulation in the cells. The effects of OAG were dose dependent at physiological diacylglycerol concentrations and were completely reversed by the protein kinase inhibitor H7. OAG, which is rapidly metabolized in cultured cells, did not protect KM12L4a cells against the cytotoxic drugs in our 96-hr in vitro chemosensitivity assay. However, rapid metabolism of diacylglycerols should not limit their capacity to activate PKC in the colonic epithelium in vivo, because that tissue is chronically exposed to replenished supplies of unsaturated diacylglycerols in the intestinal tract. Our results provide evidence that unsaturated diacylglycerols may be environmental factors that contribute to the intrinsic drug resistance of colon cancer in vivo by reducing drug accumulation in the cancer cells.
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