Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma

Venkata, Jagadish Kummetha; An, Ningfei; Stuart, Robert K.; Costa, Luciano J.; Cai, Houjian; Coker, Woodrow J.; Song, Jin H.; Gibbs, Kiwana; Matson, Terri; Garrett‐Mayer, Elizabeth; Wan, Zhuang; Öğretmen, Besim; Smith, Charles D.; Kang, Yubin

doi:10.1182/blood-2014-03-559385

Cited by 89 publications

(89 citation statements)

References 71 publications

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“…Sphingolipids are a diverse group of water-insoluble molecules that includes ceramides, sphingoid bases, ceramide phosphates and sphingoid-based phosphates [15]. The dynamic balance of ceramide phosphates and sphingoid-based phosphates determines cell proliferation, invasion and apoptosis [16].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2

et al. 2016

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MicroRNAs (miRNAs) have emerged as important gene regulators and are recognized as key players in carcinogenesis. In this study, we investigated the biological function and mechanism of miR-613 in the regulation of papillary thyroid cancer (PTC) development. We found that miR-613 was downregulated in PTC cell lines and tissues, and overexpression of miR-613 significantly suppressed PTC cell growth, migration and invasion in vitro and inhibited tumor growth in vivo. We identified the gene for sphingosine kinase 2 (SphK2) as a direct target of miR-613. Overexpression of miR-613 significantly repressed SphK2 expression by directly targeting its 3′-untranslated regions (3′-UTR) and restoration of SphK2 reversed the inhibitory effects of miR-613 on PTC cell growth and invasion. Taken together, our results indicated that miR-613 functions as a tumor suppressor in PTC and its suppressive effect is mediated by repressing SphK2 expression.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2

et al. 2016

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“…Recently, ABC294640 was shown to decrease expression of c-Myc through increased proteosomal degradation (16). Upon treatment with ABC294640, a dose-dependent decrease in c-Myc expression was observed in TRAMP-C2 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacological inhibition of SPHK2 by ABC294640 results in anti-tumor effects through various mechanisms, including apoptosis or autophagic cell death (11), inhibition of NF-κB-mediated chemotherapy resistance (12), and synergy with other cancer therapeutics (13, 14). ABC294640 can also inhibit AKT and ERK signaling, elicit anti-estrogenic effects in breast cancer cells, and increase proteasomal degradation of c-Myc (14–16). Based on promising results in preclinical models of multiple diseases, including malignancies, ABC294640 has now entered the clinic for evaluation in solid and hematologic cancers (clinicaltrials.gov identifier: NCT01488513, NCT02229981).…”

Section: Introductionmentioning

confidence: 99%

The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo

Venant

Rahmaniyan

Jones

et al. 2015

Molecular Cancer Therapeutics

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Despite recent advances in the development of novel therapies against castration resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product sphingosine-1-phosphate can promote proliferation, drug resistance, angiogenesis and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640 treated mice contained significantly higher levels of C16- and C24:1-ceramides (but not dihydro-C16-ceramide) compared to vehicle treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration resistant prostate cancer cells through both, inhibition of sphingosine kinase 2 and dihydroceramide desaturase, which provides a foundation for future exploration of this small molecule inhibitor for the treatment of advanced disease.

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“…ABC294640 was also recently shown to inhibit dihydroceramide desaturase, which accounts for the marked increases in dihydroceramides in cells treated with the drug (21, 27). The antitumor activity of ABC294640 has been demonstrated by us and others in a variety of mouse models (21, 24, 25, 27, 28, 31–37). Single-agent antitumor activity is typically apparent with doses of ABC294640 of 25 mg/kg/day or greater, and the response is associated with accumulation of the drug in the tumors, depletion of tumoral S1P levels and induction of apoptosis (21).…”

Section: Introductionmentioning

confidence: 91%

A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors

Britten

Garrett‐Mayer

Chin

et al. 2017

Clinical Cancer Research

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135

116

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Purpose Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of ABC294640, a first-in-class orally-available inhibitor of SK2. Experimental Design Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results 22 patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting and fatigue. Among the four patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and two were unable to complete Cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the Recommended Phase II Dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions At 500 mg bid, ABC294640 is well tolerated and achieves biologically-relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.

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Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma

Abstract: Key Points SK2 is overexpressed in myeloma cells and contributes to myeloma cell survival and proliferation. SK2-specific inhibitor promotes proteasome degradation of Mcl-1 and c-Myc and inhibits myeloma growth in vitro and in vivo.

Cited by 89 publications

References 71 publications

MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2

MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2

The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo

A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors

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