Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models

Abstract

Autophagy, a catabolic survival pathway, is gaining attention as a potential target in cancer. In human liver and colon cancer cells, treatment with an autophagy inducer, nanoliposomal C6-ceramide, in combination with the autophagy maturation inhibitor, vinblastine, synergistically enhanced apoptotic cell death. Combination treatment resulted in a marked increase in autophagic vacuole accumulation and decreased autophagy maturation, without diminution of the autophagy flux protein P62. In a colon cancer xenograft model, a single intravenous injection of the drug combination significantly decreased tumor growth in comparison to the individual treatments. Most importantly, the combination treatment did not result in increased toxicity as assessed by body weight loss. The mechanism of combination treatment-induced cell death both in vitro and in vivo appeared to be apoptosis. Supportive of autophagy flux blockade as the underlying synergy mechanism, treatment with other autophagy maturation inhibitors, but not autophagy initiation inhibitors, were similarly synergistic with vinblastine. Additionally, knockout of the autophagy protein Beclin-1 suppressed combination treatment-induced apoptosis in vitro. In conclusion, in vitro and in vivo data support a synergistic antitumor activity of the nanoliposomal C6-ceramide and vinblastine combination, potentially mediated by an autophagic mechanism.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Cer is the simplest molecule in this family, and it serves as a precursor for the synthesis of the three main types of complex SLs (SMs, GSLs, and gangliosides), respectively. Bioactive SLs, together with Cer, sphingosine (SPH), and sphingosine-1-phosphate (S1P), are secondary messenger molecules that regulate a diverse array of intra-and intercellular processes (3,56,60). They are important structural blocks because of their bioactive secondary messenger molecules in which they function in a different pattern of cellular processes.…”

“…Oral administration of anti-LPS antibodies along with GSLenriched adjuvant compounds was effective in ameliorating NASH and diabetes in both animal models and humans (2,3,120,124,193,194). These effects were associated with alterations of Tregs and NKT cells, thereby supporting a potential effect of GSLs on the gut-microbiome-immune system axis.…”

Synergistic combination therapy with cotylenin A and vincristine in multiple myeloma models

“…Microtubules are required for autophagosomal biogenesis and degradation, and vinca alkaloids disrupt autophagosome maturation/degradation by preventing the movement of autophagosomes and their fusion with lysosomes (18). Several studies have demonstrated that the treatment of cancers with agents that induce autophagy in combination with agents that block autophagosome maturation/degradation results in synergistic apoptotic cell death (19)(20)(21). Myeloma cells require a basal level of autophagy for survival and the pharmacologic or genetic inhibition of autophagy caused myeloma cells to die (22).…”

A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo

“…Anticancer activity was assayed against MCF-7 (human breast cancer cell line) (11). An in vitro and in vivo study suggests a synergistic anticancer activity of a nanoliposomal C6-ceramide and vinblastine combination, potentially lead by an autophagy mechanism (12).…”