Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

Radhakrishnan, Senthil K.; Halasi, Marianna; Bhat, Uppoor G.; Kurmasheva, Raushan T.; Houghton, Peter J.; Gartel, Andrei L.

doi:10.1038/sj.onc.1210692

Cited by 18 publications

(31 citation statements)

References 28 publications

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“…We showed that ARC induced potent apoptosis in transformed and cancer, but not in normal cells and exhibited potent anti-angiogenic activity in vitro [1, 3–5]. In addition, we found that ARC targets labile antiapoptotic protein, Mcl-1 [3–5] and overexpression of Mcl-1 protects cells from ARC-induced apoptosis [3, 5]. …”

Section: Introductionmentioning

confidence: 99%

ARC Synergizes with ABT-737 to Induce Apoptosis in Human Cancer Cells

Bhat

Pandit

Gartel

2010

Molecular Cancer Therapeutics

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Previously, we reported that the nucleoside analogue/transcriptional inhibitor ARC (4-amino-6-hydrazino-7-β-D-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide) was able to induce p53-independent apoptosis in multiple cancer cell lines of different origins. This occurred, at least in part, by the suppression of short-lived, prosurvival member of the Bcl-2 family, Mcl-1. In contrast, we show here that treatment of human cancer cells with the pan-Bcl-2 inhibitor ABT-737 alone led to upregulation of Mcl-1 protein expression. Combination of subapoptotic concentrations of ABT-737 and ARC induced mitochondrial injury and potent caspase-3/caspase-9-dependent apoptosis in a wide variety of human cancer cell lines. These data suggest that the ABT-737/ARC combination, which simultaneously targets Bcl-2 and Mcl-1, may be efficient against human cancer. Mol Cancer Ther; 9(6); 1688-96. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

ARC Synergizes with ABT-737 to Induce Apoptosis in Human Cancer Cells

Bhat

Pandit

Gartel

2010

Molecular Cancer Therapeutics

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“…(63) (v) Proteasome inhibitor (MG132 or MG115) has been shown to down-regulate survivin in hepatocellular carcinoma cell lines. (64) (vi) Other novel therapeutic approaches using small molecule inhibitors, nucleoside analogs, (65) or natural products or components such as betulinic acid (66) indole-3-carbinol, found in vegetables, (67) have demonstrated anticancer effects, and also been shown to downregulate survivin after treatment in certain cell lines used in respective studies.…”

Section: Modulation Of Survivin By Anticancer Drugsmentioning

confidence: 99%

Cancer cells survive with survivin

2008

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Survivin has multiple functions including cytoprotection, inhibition of cell death, and cell-cycle regulation, especially at the mitotic process stage, all of which favor cancer survival. Many studies on clinical specimens have shown that survivin expression is invariably upregulated in human cancers and is associated with resistance to chemotherapy or radiation therapy, and linked to poor prognosis, suggesting that cancer cells survive with survivin. It is also reported that survivin inhibition, alone or in combination with the other therapies, induces or enhances apoptosis and mitotic catastrophe in tumor cells. Moreover, certain antitumor agents can reduce survivin expression. These findings suggest that survivin may be a promising molecular target against human malignancies. O riginally identified as a member of the IAPs, survivin was discovered to play critical roles in cell division and cell survival.(1,2) Structurally, survivin contains a single BIR (baculoviral IAP repeats) domain, which is shared by other members of the IAPs, such as XIAP, c-IAP1, c-IAP2, and livin ( Fig. 1).(3) This domain contributes to its function in apoptosis inhibition. However, instead of a carboxyl terminal RING finger shared by others, survivin contains an extended carboxylterminal alpha-helical coiled-coil which is thought to be important for its interaction with microtubules, hence its roles in cell division.(2,4) Functioning simultaneously at cell division and apoptosis inhibition, survivin obviously plays a pivotal role in determining cell survival.Cells are programmed to die when their existence is no longer required during development or when irreparable damage occurs. Survivin counteracts this process, along with other IAPs. Survivin blocks apoptosis induced by various stimuli including FAS/ CD95, (5) irradiation, (6) and chemotherapeutic drugs, such as taxol (2) or staurosporine.(7) Inhibition of apoptosis is believed to be through direct binding to caspase-3 and caspase-7, preventing their activation.(5,8) Besides being a direct inhibitor for caspases, survivin can interact with Smac/DIABLO physically.(9) Survivin also provides cytoprotection to cells against caspase-independent cell death through the inhibition of the AIF pathway, which is known to induce caspase-independent DNA fragmentation. (10) Survivin shows cell-cycle-dependent expression during cell division. Together with Aurora-B kinase, survivin forms as component of the chromosome passenger complex, which plays a role in chromosome segregation and cytokinesis in cell division.(11) Increased survivin expression is observed in the G2/M phase. The increase in survivin expression is believed to protect cells against a possible default induction of apoptosis in the case of aberrant mitosis.(2) Survivin is also required for the maintenance of the spindle assembly checkpoint to allow proper microtubule alignment to ensure cell propagation. (12) Lack of survivin during cell division causes polyploidy as well as apoptosis (13) (Fig. 2). Polyploidy occurs following i...

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“…Transcriptional inhibitors induce apoptosis partially by inhibiting the expression of labile antiapoptotic proteins because of their ability to downregulate proteins of short half-life. 10, 13, 14, 15 The accumulation of p53 is one of the hallmarks of transcriptional stress. 11 However, transcriptional repression results in apoptosis by both p53-dependent or -independent mechanisms.…”

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confidence: 99%

Implication of transcriptional repression in compound C-induced apoptosis in cancer cells

Dai

Zhao

et al. 2013

Cell Death Dis

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Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to induce apoptosis in some types of cells. However, the underlying mechanisms remain largely unclear. Using a DNA microarray analysis, we found that the expression of many genes was downregulated upon treatment with compound C. Importantly, compound C caused transcriptional repression with the induction of p53, a well-known marker of transcriptional stress response, in several cancer cell lines. Compound C did not induce the phosphorylation of p53 but dramatically increased the protein level of p53 similar to some other transcriptional inhibitors, including 5,6-dichloro-1-β-D-ribobenzimidazole (DRB). Consistent with previous reports, we found that compound C initiated apoptotic death of cancer cells in an AMPK-independent manner. Similar to DRB and actinomycin D (ActD), two classic transcription inhibitors, compound C not only resulted in the loss of Bcl-2 and Bcl-xl protein but also induced the phosphorylation of eukaryotic initiation factor-alpha (eIF2α) on Ser51. Hence, the phosphorylation of eIF2α might be a novel marker of transcriptional inhibition. It is noteworthy that compound C-mediated apoptosis of cancer cells is correlated with decreased expression of Bcl-2 and Bcl-xl and the phosphorylation of eIF2α on Ser51. Remarkably, compound C exhibits potent anticancer activities in vivo. Taken together, our data suggest that compound C may be an attractive candidate for anticancer drug development.

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Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

Cited by 18 publications

References 28 publications

ARC Synergizes with ABT-737 to Induce Apoptosis in Human Cancer Cells

ARC Synergizes with ABT-737 to Induce Apoptosis in Human Cancer Cells

Cancer cells survive with survivin

Implication of transcriptional repression in compound C-induced apoptosis in cancer cells

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