The “survivin suppressants” NSC 80467 and YM155 induce a DNA damage response

Glaros, Trevor; Stockwin, Luke H.; Mullendore, Michael E.; Smith, Brian A.; Morrison, Bethanie L.; Newton, Dianne L.

doi:10.1007/s00280-012-1868-0

Cited by 86 publications

(116 citation statements)

References 15 publications

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“…Recent findings have shown that the uptake of YM155 into cells was dependent on the presence of a specific solute carrier SLC35F2 and it is conceivable that varying levels of this transporter on the outer membrane surfaces of tumoral cells could have moderated the cytotoxicity of YM155 [28]. Various reports have since questioned if the suppression of survivin is the sole and main effect of YM155-induced cytotoxicity [21,26,28]. The consensus is that YM155 is a DNA intercalating agent and induces a DNA damage response that leads to apoptotic cell death.…”

Section: Discussionmentioning

confidence: 97%

“…YM155 was reported to intercalate with DNA and to induce a DNA damage response which is purportedly central to its anticancer properties [26,28]. In the presence of YM155, prostate cancer cells PC3 showed dose dependent increases in two biomarkers of DNA damage, phosphorylated histone gH2AX and phosphorylated KAP1.…”

Section: Formation Of Gh2ax In Treated Cellsmentioning

confidence: 98%

“…A transcriptome analysis of Wilms' tumor cells treated with YM155 revealed down-regulation of several other genes besides survivin as well as the up-regulation of the pro-apoptotic genes caspase 9 and DIABLO [25]. More critically, reports have surfaced that YM155 increased levels of the DNA damage markers gH2AX and phosphorylated KAP1 in malignant cells [26,27]. This has led to the proposal that YM155 acts primarily by inducing DNA damage and that any effect on survivin is a secondary event caused by the general deactivation of gene expression brought about by DNA damage [26].…”

Section: Introductionmentioning

confidence: 95%

“…More critically, reports have surfaced that YM155 increased levels of the DNA damage markers gH2AX and phosphorylated KAP1 in malignant cells [26,27]. This has led to the proposal that YM155 acts primarily by inducing DNA damage and that any effect on survivin is a secondary event caused by the general deactivation of gene expression brought about by DNA damage [26].…”

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure–activity relationship study

Sim

Yee

et al. 2015

European Journal of Medicinal Chemistry

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Section: Discussionmentioning

confidence: 97%

Section: Formation Of Gh2ax In Treated Cellsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure–activity relationship study

Sim

Yee

et al. 2015

European Journal of Medicinal Chemistry

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“…Glaros and colleagues first reported that YM155 was a DNA damaging agent rather than a transcriptional suppressor of survivin , because the concentrations of YM155 required to induce γH2AX and P-KAP1, two hallmarkers of DNA damage response, were much lower than that needed to inhibit survivin [49]. YM155-induced downregulation of survivin was likely a secondary event following DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia

Huang¹,

Lyu

Wang

2015

Cancer Letters

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Overexpression of survivin is observed in various hematological malignancies, including acute myeloid leukemia (AML). Studies show that elevated expression of survivin correlates with a worse clinic outcome in AML patients. It remains unclear whether inhibition of survivin may alter the efficacy of chemotherapy against AML. Here, we evaluate the effects of specific knockdown of survivin on AML cells’ sensitivity to chemotherapy, and investigate the therapeutic potential of the transcription inhibitor of survivin YM155 either alone or in combination with chemotherapeutic agents. We found Kasumi-1 and HL-60 cells had relatively higher expression levels of survivin among all AML cell lines tested. Specific knockdown of survivin in Kasumi-1 and HL-60 cells resulted in: inhibition of cell proliferation; cell cycle G2/M arrest; induction of DNA damage response and apoptosis. Downregulation of survivin enhanced etoposide- or doxorubicin-induced anti-proliferative/anti-survival activity in AML cells. The small molecule inhibitor YM155 reduced survivin in a dose- and time-dependent manner and trigged apoptosis in Kasumi-1 and HL-60 cells. The combinatorial effects of YM155 and chemotherapeutics were either synergetic or antagonistic, depending upon the drugs used for combination and the type of AML cells being treated. Collectively, our data demonstrate that survivin plays an important role in the maintenance and proliferation of AML cells. While specific knockdown of survivin enhances chemosensitivity, the combinations of YM155 and chemotherapeutic agents exhibit synergetic or antagonistic effects on AML cells. Our findings provide a rationale for further assessment of survivin-targeted therapy in the treatment of patients with AML.

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Oxyphenisatin acetate (NSC59687) triggers a cell starvation response leading to autophagy, mitochondrial dysfunction, and autocrineTNFα‐mediated apoptosis

et al. 2013

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Oxyphenisatin (3,3-bis(4-hydroxyphenyl)-1H-indol-2-one) and several structurally related molecules have been shown to have in vitro and in vivo antiproliferative activity. This study aims to confirm and extend mechanistic studies by focusing on oxyphenisatin acetate (OXY, NSC 59687), the pro-drug of oxyphenisatin. Results confirm that OXY inhibits the growth of the breast cancer cell lines MCF7, T47D, HS578T, and MDA-MB-468. This effect is associated with selective inhibition of translation accompanied by rapid phosphorylation of the nutrient sensing eukaryotic translation initiation factor 2α (eIF2α) kinases, GCN2 and PERK. This effect was paralleled by activation of AMP-activated protein kinase (AMPK) combined with reduced phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6K and 4E-BP1. Microarray analysis highlighted activation of pathways involved in apoptosis induction, autophagy, RNA/protein metabolism, starvation responses, and solute transport. Pathway inhibitor combination studies suggested a role for AMPK/mTOR signaling, de novo transcription and translation, reactive oxygen species (ROS)/glutathione metabolism, calcium homeostasis and plasma membrane Na+/K+/Ca2+ transport in activity. Further examination confirmed that OXY treatment was associated with autophagy, mitochondrial dysfunction, and ROS generation. Additionally, treatment was associated with activation of both intrinsic and extrinsic apoptotic pathways. In the estrogen receptor (ER) positive MCF7 and T47D cells, OXY induced TNFα expression and TNFR1 degradation, indicating autocrine receptor-mediated apoptosis in these lines. Lastly, in an MCF7 xenograft model, OXY delivered intraperitoneally inhibited tumor growth, accompanied by phosphorylation of eIF2α and degradation of TNFR1. These data suggest that OXY induces a multifaceted cell starvation response, which ultimately induces programmed cell death.The mechanistic basis for oxyphenisatin acetate anti-cancer activity remains unresolved. This study demonstrates that exposure is associated with an acute nutrient deprivation response leading to translation inhibition, induction of autophagy, transient estrogen receptor (ER) stress and mitochondrial dysfunction. Ultimately these effects promote apoptosis induction, which in ER+ breast cancer cells is mediated by autocrine TNFα production. This is the first study implicating a nutrient deprivation response as central to the downstream effects of oxyphenisatin acetate.

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The “survivin suppressants” NSC 80467 and YM155 induce a DNA damage response

Abstract: These data provide the first evidence that NSC80467 and YM155 are DNA damaging agents where suppression of survivin is a secondary event, likely a consequence of transcriptional repression.

Cited by 86 publications

References 15 publications

Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure–activity relationship study

Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure–activity relationship study

Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia

Oxyphenisatin acetate (NSC59687) triggers a cell starvation response leading to autophagy, mitochondrial dysfunction, and autocrineTNFα‐mediated apoptosis

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