JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells

Abstract

IntroductionMultiple myeloma (MM) is a B-cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow (BM). Despite the recent emergence of novel therapies including bortezomib, 1,2 thalidomide, 3,4 and lenalidomide, 5 it remains incurable due to the development of drug resistance. [5][6][7] Among the factors that lead to this resistance are defects in apoptotic signaling pathways and overexpression of the multidrug resistance protein (MRP) pumps that enhance drug efflux. 8 In addition, the BM microenvironment confers drug resistance in MM via (1) secretion of cytokines such as interleukin 6 (IL-6) and insulin-like growth factor 1 (IGF-1), which mediate survival signals in MM cells, 9-11 as well as (2) direct interaction with MM cells, which results in cell adhesion-mediated drug resistance. 12,13 Despite recent progress, MM remains incurable, and new therapeutic agents with novel mechanism of actions are urgently needed.JS-K (O 2 -(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate) belongs to a diazeniumdiolate class of prodrug designed to release nitric oxide (NO • ) when metabolized by glutathione S-transferases (GSTs; Figure 1A). 14 GSTs are enzymes that catalyze the conjugation of xenobiotics with glutathione (GSH), thereby facilitating their subsequent efflux through MRP pumps. 15 GSTs are frequently overexpressed in a broad spectrum of tumors. 16,17 In the context of conventional chemotherapy, this provides tumor cells with a selective survival advantage over normal cells by enhancing drug efflux and thus decreasing therapeutic efficacy. In contrast, since JS-K uniquely requires GST for its optimal activity, it can potentially turn GST overexpression to the tumor's disadvantage by generating relatively high intracellular concentrations of cytotoxic NO • , specifically within tumor cells. Importantly, JS-K has recently been shown to inhibit tumor growth in both in vitro and in vivo models of human prostate cancer and human leukemia. 14 Importantly, GSTs are overexpressed in 10% to 70% of patients with MM at diagnosis, and in 30% of patients at relapse. 8 In addition, in our recent study comparing gene expression profiles of patient MM cells with normal plasma cells from a genetically identical twin, we observed that GST was overexpressed by 7-fold in MM cells. 18 Furthermore, in our high-resolution genomic and expression profiling of primary tumor cells from 67 patients with MM and plasma cells from 12 healthy donors, 19 33% and 39% of the MM cells overexpressed GSTP1 and GSTM1, respectively, when compared with plasma The online version of this manuscript contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From cell controls. To date, however, the biological effects of JS-K on MM cells ha...

Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

“…EndoG and AIF have been reported to be caspase-independent death effectors 16,17 and play important roles in caspaseindependent apoptosis of osteosarcoma, 43 multiple myeloma 44 and breast cancer cells. 45 Until now, only AIF has been reported to be involved in caspase-independent apoptosis induced by cisplatin.…”

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

“…Reportedly, JNK activation is one of the crucial pathways for apoptosis induction by the leading anti-MM agents such as proteasome inhibitors or IMiDs, or various new candidate agents for MM. 16,[25][26][27][28][29] Also, various new candidate anti-MM agents, such as the histone deacetylase inhibitor PXD101, induce apoptosis by activating the p38 MAPK pathway in myeloma cells. [30][31][32][33] These findings lead us to suggest that both JNK and p38 pathways activation are the logical molecular targets for the development of new therapeutic strategies for MM.…”

“…[11][12][13][14][15] In this study, we show the anti-multiple myeloma (MM) activity of a recombinant mutant form of human galectin-9 (hGal9) through the activation of c-Jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, those share crucial roles in the survival and death of myeloma cells. 16 …”

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

“…This compound, a novel nitrate containing an NSAID and disulfide pharmacophores, exhibits antiproliferative activity and exerts a G 2 /M cell cycle block in cultured colon cancer cells [13]. Finally, the so-called NONO-NSAIDs have been synthesized and studied for their anti-inflammatory and anticancer properties [14][15][16]. It should not be forgotten that the organic nitrates are also NO-donating compounds.…”