Abstract
The identification of novel combinations of effective cancer drugs is required for the successful treatment of cancer patients for a number of reasons. First, many “cancer specific” therapeutics display detrimental patient side-effects and second, there are almost no examples of single agent therapeutics that lead to cures. One strategy to decrease both the effective dose of individual drugs and the potential for therapeutic resistance is to combine drugs that regulate independent pathways that converge on cell death. BCL2-like family members are key proteins that regulate apoptosis. We conducted a screen to identify drugs that could be combined with an inhibitor of anti-apoptotic BCL2-like proteins, ABT-263, to kill human leukemia cells lines. We found that the combination of D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) hydrochloride, an inhibitor of glucosylceramide synthase, potently synergized with ABT-263 in the killing of multiple human leukemia cell lines. Treatment of cells with PDMP and ABT-263 led to dramatic elevation of two pro-apoptotic sphingolipids, namely ceramide and sphingosine. Furthermore, treatment of cells with the sphingosine kinase inhibitor, SKi-II, also dramatically synergized with ABT-263 to kill leukemia cells and similarly increased ceramides and sphingosine. Data suggest that synergism with ABT-263 requires accumulation of ceramides and sphingosine, as AMP-deoxynojirimycin, (an inhibitor of the glycosphingolipid pathway) did not elevate ceramides or sphingosine and importantly did not sensitize cells to ABT-263 treatment. Taken together, our data suggest that combining inhibitors of anti-apoptotic BCL2-like proteins with drugs that alter the balance of bioactive sphingolipids will be a powerful combination for the treatment of human cancers.
Highlights
Cancer cells are a distorted version of their normal counterparts [1]
Of interest to our lab was that a known modulator of ceramide metabolism D,L-threo-1phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) hydrochloride that ranked among the highest synergy scores across all three cell lines
Isobologram analysis demonstrated that the combination idex (CI) of the points corresponding to 2 mM of ABT-263 and 45 mM of PDMP was less than 0.1
Summary
One of the important distortions that separate cancer cells from healthy cells is the inability to undergo programmed cell death, or apoptosis, triggered by homeostatic processes. High doses of toxic compounds have been used, and are still used, to eradicate cancers; the unwarranted consequences of this type of regimen are the detrimental side effects that patients experience due to the death of normal cells of the body. The first is the BCL2-family of proteins and the second are bioactive sphingolipids. Both families can be sub-divided into members that possess the ability to either cause or prevent apoptosis and modulators of these molecules are being explored as potential cancer therapeutics [2,3,4,5]
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