Oncotarget: TAK1-inhibitors are cytotoxic for multiple myeloma cells

IMPACT JOURNALS LLC

IMAGE: NG25 REDUCE VIABILITY OF CD138+ CELLS FROM PATIENTS, ALONE AND IN COMBINATION WITH MELPHALAN. (A) CD138+ CELLS FROM 10 INDIVIDUAL DONORS WERE TREATED WITH NG25 BEFORE CELL VIABILITY WAS MEASURED. INDIVIDUAL DONORS, MEAN, AND SD ARE SHOWN. ASTERISKS INDICATE STATISTICALLY SIGNIFICANT DIFFERENCES (KRUSKAL-WALLIS TEST, DUNN’S MULTIPLE COMPARISON TEST, P < 0,05). (B) CD138+ CELLS FROM 10 INDIVIDUAL DONORS WERE TREATED WITH MELPHALAN, NG25 OR BOTH IN TECHNICAL TRIPLICATES. MEAN AND SD OF TRIPLICATES FROM EACH DONOR ARE SHOWN. SINGLE ASTERISK DENOTES STATISTICAL SIGNIFICANCE AS COMPARED TO THE CONTROL NOT TREATED WITH NG25 FOR THE LOWEST DOSE OF NG25, DOUBLE ASTERISK DENOTES STATISTICAL SIGNIFICANCE AS COMPARED TO THE UNTREATED CONTROL FOR THE HIGHEST DOSE OF NG25. ASTERISKS INDICATE STATISTICALLY SIGNIFICANT DIFFERENCES (TWO-WAY ANOVA, TUKEY’S MULTIPLE COMPARISON TEST, P < 0,05). ALL TREATMENTS WERE FOR 18 HOURS, AND VIABILITY WAS MEASURED BY CELLTITER-GLO.

CREDIT: CORRESPONDENCE TO – KRISTIAN K. STARHEIM – [email protected]

Oncotarget published “TAK1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan” which reported that TAK1 is an attractive drug target as it switches these survival pathways to cell death. NG25 reduced expression of MYC and E2F controlled genes, involved in tumor cell growth, cell cycle progression, and drug resilience.

TAK1 can be activated by genotoxic stress. NG25 and 5Z-7 induced both synergistic and additive cytotoxicity in combination with the alkylating agent melphalan.

Melphalan activated TAK1, NF-B, and the MAPKs p38 and c-Jun N-terminal kinase, as well as a transcriptional UV-response. This was blocked by NG25, and instead apoptosis was activated.

In sum, TAK1 is a promising drug target for MM treatment.

Dr. Kristian K. Starheim from Trondheim, Norway said, “Multiple myeloma (MM) is the second most common hematological malignancy worldwide.”

The overall survival time of multiple myeloma has improved in the later years due to novel therapeutic strategies. It induces expression of survival factors through nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen activated protein kinases.

Targeting the kinases upstream in the signaling pathway, such as TAK1, has been proposed. TAK1 restrains receptor-interacting serine/threonine-protein kinase 1 dependent cell death, and inhibition of activated TAK1 shifts cells from pro-survival programs to cell death, making it an attractive drug target.

TAK1-inhibition has shown promising results in MM, but with limited investigation. Here, the authors show that the TAK1-inhibitors NG25 and 5Z-7 reduce viability of MM cell lines and primary cells. The combination of TAK1 inhibitors with melphalan or other DNA-damaging agents increases the cytotoxicity in a synergistic or additive manner. TAK1-inhibitors also reduced the number and viability of osteoclasts, suggesting that they have an additional positive effect on MBD.

Their findings suggest that TAK1-inhibitors in combination with DNA-damaging agents represent a potential treatment strategy in MM patients.

The Starheim Research Team concluded in their Oncotarget Research Output, “TAK1-inhibitors reduce MM cell viability and induce apoptosis through several mechanisms. They potently induce cell death in combination with melphalan and reduce OC numbers and viability. TAK1 is an interesting candidate for further clinical testing as a drug target in MM.”