Targeting acid sphingomyelinase with anti-angiogenic chemotherapy

Abstract

Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase+/+, but not in asmase−/−, hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1–2 hours before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.

Acid sphingomyelinase deficiency enhances myelin repair after acute and chronic demyelination

“…[ 27 ] Fibroblast growth factors (FGF) are important enhancing factors of myelin growth. [ 20 , 21 , 22 ] Previous studies have shown that FGF blocks Asm activation [ 28 ], and the beneficial effects of FGF might be, at least in part, mediated by an interaction with the Asm/ceramide system. Corroborating this hypothesis is our finding that the myelin growth factors FGF-1 and FGF-2 are significantly increased in the recovery phase after acute demyelination in mice lacking Asm , suggesting that the Asm/ceramide system negatively regulates FGF after demyelination.…”

Stromal Fibroblasts Counteract the Caveolin-1-Dependent Radiation Response of LNCaP Prostate Carcinoma Cells

“…Especially the increased secretion patterns of lysosomal proteins such as ASMase, arylsulfatase A and more specifically of lysosomalassociated membrane proteins already indicated higher lysosomal exocytosis activities in more reactive (CAV1-deficient) fibroblasts (13,16). The higher (stromal) secretion of ASMase in turn could foster the formation of ceramide-enriched membrane platforms on tumor cells, and thus allowing associated receptors to cluster here finally altering the cells signaling in terms of promoting resistance (80,81). Finally, the CAV1-dependent stromal support of PCa cells was shown to comprise a feeding with resistance factors, e.g., apoptosis inhibiting proteins (13,16).…”

Antineoplastic Agents Targeting Sphingolipid Pathways

“…Cytarabine, a drug used to treat acute myeloid leukemia, has been shown to increase ceramide levels via de novo synthesis (89). The classic chemotherapy drugs anthracyclines, etoposide and paclitaxel have each been shown to induce acid sphingomyelinase (90), leading to increased ceramide from the hydrolysis of sphingomyelin. However, it is unclear whether or not the activation of sphingomyelinase in each of these instances is responsible for inducing apoptosis, but rather may just be a response to cellular stress (91).…”

“…In a complex interplay between ceramide glycosylation, ceramide induced apoptosis, and p-glycoprotein, studies have shown that expression of p-glycoprotein confers resistance to ceramide toxicity (94), and that overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance chemotherapy (95). These findings imply that GCS inhibitors such as Tamoxifen, vincristine, doxorubicin, and Taxol will likely function as a sensitizer to drug resistant cancers (90). Indeed, this topic has been studied extensively with many completed and ongoing clinical trials in various stages of progression.…”