Differential regulation of autophagy and cell viability by ceramide species

The present studies sought to determine whether the anti-folate pemetrexed (Alimta) and the sphingosine-1-phosphate receptor modulator FTY720 (Fingolimod, Gilenya) interacted to kill tumor cells. FTY720 and pemetrexed interacted in a greater than additive fashion to kill breast, brain and colorectal cancer cells. Loss of p53 function weakly enhanced the toxicity of FTY720 whereas deletion of activated RAS strongly or expression of catalytically inactive AKT facilitated killing. Combined drug exposure reduced the activity of AKT, p70 S6K and mTOR and activated JNK and p38 MAPK. Expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the interaction between FTY720 and pemetrexed. Treatment of cells with FTY720 and pemetrexed increased the numbers of early autophagosomes but not autolysosomes, which correlated with increased LC3II processing and increased p62 levels, suggestive of stalled autophagic flux. Knock down of ATG5 or Beclin1 suppressed autophagosome formation and cell killing. Knock down of ceramide synthase 6 suppressed autophagosome production and cell killing whereas knock down of ceramide synthase 2 enhanced vesicle formation and facilitated death. Collectively our findings argue that pemetrexed and FTY720 could be a novel adjunct modality for breast cancer treatment.     

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists

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Reversible cerebral vasoconstriction syndrome in association with fingolimod use

Background: Reversible cerebral vasoconstriction syndrome (RCVS), also known as Call-Fleming syndrome, is characterized by thunderclap headaches, non-aneurysmal segmental cerebral vasoconstriction seen on arteriogram, and spontaneously resolves within 12 weeks. Fingolimod has been reported to cause posterior reversible encephalopathy syndrome (PRES) and one case of RCVS. Objective: We report a case of RCVS possibly related to fingolimod use, and compare to cases of adverse outcomes in fingolimod use. Methods: This is a single observational study without controls; therefore, level of evidence is IV. A literature review in pubmed with keywords, fingolimod, vasospasm, RCVS, Call-Fleming, stroke, PRES and hemorrhage. Results: One case of RCVS on fingolimod in the post-partum period. Two other cases in the literature were found one with hemorrhagic encephalitis and the other critical vasospasm in the upper extremity associated with fingolimod 1.25 mg daily in the FREEDOMS II trial and TRANSFORMS study, respectively. Additionally, Novartis reports nine cases of PRES related to fingolimod use. Conclusion: Fingolimod has the potential to cause vasoconstriction however appears to be rare and more likely on doses higher than 0.5 mg daily. Fingolimod may be associated in RCVS and should be considered in patients with severe headache on fingolimod.