Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells

Abstract

Daunorubicin (as well as other anthracyclines) is known to be toxic to heart cells and other cells in organism thus limiting its applicability in human cancer therapy. To investigate possible mechanisms of daunorubicin cytotoxicity, we used stem cell lines derived from adult rabbit skeletal muscle. Recently, we have shown that daunorubicin induces apoptotic cell death in our cell model system and distinctly influences the activity of MAP kinases. Here, we demonstrate that two widely accepted antagonistic signalling pathways namely proapoptotic JNK and prosurvival PI3K/AKT participate in apoptosis. Using the Western blot method, we observed the activation of JNK and phosphorylation of its direct target c-Jun along with inactivation of AKT and its direct target GSK in the course of programmed cell death. By means of small-molecule kinase inhibitors and transfection of cells with the genes of the components of these pathways, c-Jun and AKT, we confirm that JNK signalling pathway is proapoptotic, whereas AKT is antiapoptotic in daunorubicin-induced muscle cells. These findings could contribute to new approaches which will result in less toxicity and fewer side effects that are currently associated with the use of daunorubicin in cancer therapies.

The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents

“…DNR can alter cell signaling through sphingomyelin-ceramide, MAPK, c-Jun N-terminal kinase, nuclear factor kB, and PI3K/AKT pathways 48 and can inactivate AKT signaling in muscle cells. 49 The specific mechanisms underlying cooperativity between dasatinib and DNR in AML cells require additional investigation, although DNR treatment did modestly increase SFK inhibition in combination with dasatinib. Mechanisms other than p53 activation may also contribute to cooperativity.…”

Long‐term muscle‐derived cell culture: multipotency and susceptibility to cell death stimuli

“…Unlimited proliferation potential of muscle‐derived cells proved their stemness. Previously we mainly focused on the mechanisms determining death/survival processes in adult stem cells (Baltriukiene et al, ; Stulpinas et al, ; Bironaite et al, ). Feasibility and safety of Myo cells use in therapy after long‐term culturing was confirmed by investigations in vivo after Myo cell transplantation into infarcted myocardium of rabbits (Bukelskiene et al, ; Sirmenis et al, ).…”

A linear programming computational framework integrates phosphor-proteomics and prior knowledge to predict drug efficacy

“… Daunorubicin [ 31 ], a market selling heterocyclic anticancer drug, mainly activate MAPK (MEK/ERK, and JNK) pathways via ER→SHC→RAS, and down-regulated cell survival through reduced PI3K/AKT pathway in the inferred MCF7-specific pathway network (Additional file 5 : Figure S4). Stulpinas and colleagues observed that daunorubicin treatment induced the activation of JNK and phosphorylation of its direct target c-Jun along with inactivation of AKT [ 32 ]. We also noticed from Additional file 5 : Figure S4 that, the activation of HDAC1 induced the down-regulation of p53.…”