Proteasomal Degradation of Topoisomerase I Is Preceded by c-Jun NH2-Terminal Kinase Activation, Fas Up-Regulation, and Poly(ADP-Ribose) Polymerase Cleavage in SN38-Mediated Cytotoxicity against Multiple Myeloma

Abstract

ABSTRACT

Aggresome induction by proteasome inhibitor bortezomib and α-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells

“…The cytoplasmic appearance of diffuse acetyl-␣-tubulin (arrowhead) is a nonspecific feature of apoptosis that was also observed when cells were treated with topoisomerase inhibitors, which induce cell death in MM cells in a caspase-dependent manner. 53 The Figure 5B center panel shows hyperacetylated segmented ␣-tubulin, and the right panel shows a mitotic figure (arrow) with marked disruption of equatorial plate formation versus the normal mitotic figure featured in Figure 5A, confirming the disruptive effects of HDAC inhibition on chromosomal alignment and the MTOC during For personal use only. on May 7, 2018.…”

“…In general, caspase-mediated apoptosis is triggered via initiator caspases (caspase-8 and -9) and downstream effector caspases (caspase-3, -6, and -7), and occurs when the activity of proapoptotic molecules such as reactive oxygen species (ROS) overcome antiapoptotic mechanisms, such as activation of nuclear factor -B. Synergy has been observed between bortezomib and the anthracycline antibiotic doxorubicin via inhibition of DNA repair enzymes, 54 and between bortezomib and the topoisomerase-1 inhibitor SN38 via inhibition of nuclear factor -B. 53,55 Synergistic apoptosis induced by bortezomib in combination with SAHA and sodium butyrate is mediated via mitochondrial dysfunction and ROS-dependent mechanisms, and downstream events include nuclear factor -B inactivation, c-Jun NH terminal kinase activation, p53 induction, caspase activation, PARP cleavage, and caspase-dependent cleavage of p21, p27, bcl-2, mcl-1, X-linked inhibitor of apoptosis, and down-regulation of cyclin D1. 6,56 Therefore, a number of potential molecular mechanisms may contribute to mediating the synergy between bortezomib and LBH589.…”

Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib

“…Thrombospondin-1 increases the level of Fas ligand on endothelial cells (Volpert et al, 2002;Yap et al, 2005). Moreover, it has been described that SN-38 induces Fas upregulation and caspase 8-mediated apoptosis in multiple myeloma cells (Catley et al, 2004). Thus, the low-dose SN-38 may also increase Fas ligand through the increase of TSP-1 secretion and, maybe, the Fas receptor such as other low doses chemotherapeutic drugs.…”

1-Methoxy-Canthin-6-One Induces c-Jun NH2-Terminal Kinase–Dependent Apoptosis and Synergizes with Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Activity in Human Neoplastic Cells of Hematopoietic or Endodermal Origin

“…The mechanism of 1-methoxycanthin-6-one activity seemed to entirely rely on JNK activation; indeed, the inhibition of the kinase was able to completely prevent apoptosis induced by the compound. In this respect, these findings provide one of the clearest evidence attesting that JNK activation can exert a major role in the activity of antineoplastic molecules (19)(20)(21)(22)(23)(24)(25)(26)(27).…”

“…The activity of JNK influences cell apoptosis (6,(14)(15)(16)(17)(18) and mediates the proapoptotic effects of some antineoplastic compounds (19)(20)(21)(22)(23)(24)(25)(26)(27). Furthermore, it regulates the expression of TRAIL-R2 (DR5; refs.…”