Melanoma Pathways

Study - Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells

The tumor suppressor protein p53 is often inhibited in melanoma due to the overexpression of Mdm2 or MdmX. However, Treatment with albendazole (AB) and fenbendazole (FB) increased the level of p53 and decreased the levels of Mdm2 and MedmX in cells that overexpressed these proteins.  AB and FB MAY be helpful in cancers that overexpress p53 suppressors. However, FB has been shown to promote cancer growth in some cancers including colorectal cancer. Several people have experienced shrinkage of their cancer initially and then rapid growth after a short time. I advise caution when using off-label drugs like FB. 

"In summary, we established a new tool for testing the impact of small molecule compounds on the activity of p53 and used it to identify the action of benzimidazoles in melanoma cells. The drugs promoted the stability and transcriptional activity of wild-type p53 via downregulation of its negative regulators Mdm2 and MdmX in cells overexpressing these proteins. The results indicate the potential for repurposing the benzimidazole anthelmintics for the treatment of cancers overexpressing p53 negative regulators."

https://www.mdpi.com/1420-3049/24/11/2152/pdf-vor

 

Study - Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells.

"Our data reveal that mebendazole inhibits melanoma growth with an average IC(50) of 0.32 micromol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes... We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent."

https://www.ncbi.nlm.nih.gov/pubmed/18667591

Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling

 

 

Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth.

"Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized "precision diets" that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299059/

Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling

https://reader.elsevier.com/reader/sd/pii/S0167488916300155?token=52A05B807B4BB954C8B92E9E2AEECAB5F48E8B2FD814728B5A3F7E1B353DD095ACAB1B65B514144DE46B693F5A9E1EB1

​Study - Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent

In this rat study mebendazole had no side effects and was as effective as the chemotherapeutic drug Temodar!

"MBZ also had the greatest inhibitory effect against the melanoma cells of the four benzimidazoles tested.

Subsequently, MBZ was shown to inhibit human melanoma xenograft growth in athymic female nude mice fed 1 mg or 2 mg oral MBZ every other day [18]. Tumour growth was reduced by 83% for the 1 mg dose and 77% for the 2 mg in comparison to controls. This was comparable to the growth inhibitory activity of 100 mg/kg of temozolomide (TMZ) by an intraperitoneal injection for 5 days, used as a positive control as it represents a well-characterised option for melanoma treatment. These results showed that oral MBZ produced equivalent responses to high-dose TMZ, but with no observed side effects."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/

Targeting CPT1A enhances metabolic therapy in human melanoma cells with the BRAF V600E mutation.

https://www.ncbi.nlm.nih.gov/pubmed/27793752

"Let food be thy medicine and medicine be thy food" - Hippocrates