Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

Rough, James J.; Monroy, Manuel; Yerrum, Smitha; Daly, J.M.

doi:10.1186/1757-2215-3-13

Cited by 42 publications

(30 citation statements)

References 27 publications

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“…26Y28 We aimed to test how T0901317 may enhance cisplatin efficacy as a combination treatment. However, unlike previous reports, 26,28 we observe that T0901317 has very little influence on cell growth when used alone but significantly increases the IC 50 of both cisplatin and paclitaxel it is added in combination. In the A2780-cp cell line, selected for drug resistance, the effect of T0901317 is abrogated, suggesting that T0901317-regulated pathways are important contributors to cisplatin sensitivity in the parental A2780 cell line.…”

Section: Discussioncontrasting

confidence: 99%

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T090137 Inhibits Cisplatin-Induced Apoptosis in Ovarian Cancer Cells

Miller

Fischer

Chu

et al. 2011

International Journal of Gynecological Cancer

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Objective To determine the function of T0901317 in combination treatment with cisplatin in ovarian cancer cells. Methods We screened the effects of three nuclear hormone receptor ligands on cell viability in a panel of ovarian cancer cells lines. T0901317 regulation of apoptosis and cell cycle regulators was determined when applied as a single agent, or in combination with cisplatin. Results Surprisingly, the LXR agonist T0901317 had no significant effects on a panel of seven ovarian cancer cell lines as a single agent. T0901317 does, however, significantly decrease cisplatin efficacy in at least three ovarian cancer cells lines. T0901317 reduces cisplatin induced apoptosis and reverses cisplatin induced expression of cell cycle regulators. T0901317 appears to work in an LXR, PXR, and FXR independent manner, as agonists of these nuclear hormone receptors did not show similar effects. Interestingly, in the A2780-cp drug resistant cell line, the effect of T0901317 is lost, suggesting that the pathways stimulated by T0901317 to reduce cisplatin efficacy could be inherently active features of the selected resistance. Conclusions Together, these data suggest that T0901317 inhibits cisplatin in some ovarian cancer cells. These data provide an avenue to investigate when T0901317 may be acting to promote tumor survival and drug resistance through control of apoptosis, and when it may be acting as an anti-tumor agent, as has been previously reported.

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Section: Discussioncontrasting

confidence: 99%

“…These data differ from previous reports of antiproliferative effects of T0901317 where very high concentrations were used. 12,26 At concentrations greater than 20 Kmol/L, we also observe T0901317 antiproliferative effects. We observe T0901317-protective effects in the 1-to 10-Kmol/L range.…”

Section: Discussionmentioning

confidence: 56%

T090137 Inhibits Cisplatin-Induced Apoptosis in Ovarian Cancer Cells

Miller

Fischer

Chu

et al. 2011

International Journal of Gynecological Cancer

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“…Induction of intrinsic apoptosis by LXR agonists was previously described in ovarian carcinoma cells, 45 and confirmed here associated with a significant increase of BAX and BAK1 transcripts (encoding proapoptotic proteins). LXR-induced cell death in breast cancer cells has been demonstrated to implicate BAX upregulation and to be dependent on cholesterol efflux through ABCG1.…”

Section: Discussionmentioning

confidence: 48%

“…39,42,43 Concentrations higher than 10 mM induced a significant BPDCN cell death, as reported for ovarian, breast, and colon cancer cells. [43][44][45] All of these data validate the concentrations of LXR agonists used in this study.…”

Section: Discussionmentioning

confidence: 54%

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Ceroi

Masson

Roggy

et al. 2016

Blood

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Key Points• LXR activation inhibits BPDCN cell survival through the increase of cholesterol efflux, the inhibition of NF-kB, and IL-3 signaling.• Treatment with LXR agonists can be proposed as a new therapeutic approach for BPDCN.Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-kB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach. (Blood. 2016;128(23):2694-2707

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“…LXR agonists have been demonstrated to significantly lower intracellular cholesterol levels in cancer cells and therefore exhibit anti-neoplastic activity (Chuu and Lin, 2010; Rough et al, 2010). As a result, LXR agonists have been extensively investigated as pre-clinical anti-cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

et al. 2015

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SUMMARY Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.

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Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

Cited by 42 publications

References 27 publications

T090137 Inhibits Cisplatin-Induced Apoptosis in Ovarian Cancer Cells

T090137 Inhibits Cisplatin-Induced Apoptosis in Ovarian Cancer Cells

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

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