| Reference | 1. Mol Cancer Ther. 2017 Dec;16(12):2724-2734. doi: 10.1158/1535-7163.MCT-17-0485.
Epub 2017 Sep 22.
<br><br>
ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic
Virus-Infected Cell Autophagic Death and Represses Tumor Growth.
<br><br>
Dai L(1)(2), Bai A(3), Smith CD(4), Rodriguez PC(5), Yu F(6), Qin Z(7)(2).
<br>
Author information: <br>
(1)Department of Pediatrics, Research Center for Translational Medicine and Key
Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine,
Shanghai, China.
(2)Department of Genetics, Louisiana State University Health Sciences Center,
Louisiana Cancer Research Center, New Orleans, Louisiana.
(3)Department of Biochemistry and Molecular Biology, Hollings Cancer Center,
Medical University of South Carolina, Charleston, South Carolina.
(4)Apogee Biotechnology Corporation, Hershey Center for Applied Research,
Hummelstown, Pennsylvania.
(5)H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
(6)Department of Clinical Laboratory, Shanghai Pulmonary Hospital, Tongji
University School of Medicine, Shanghai, China. [email protected] [email protected].
(7)Department of Pediatrics, Research Center for Translational Medicine and Key
Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine,
Shanghai, China. [email protected] [email protected].
<br>
Kaposi sarcoma-associated herpes virus (KSHV) is the etiologic agent of several
malignancies, including Kaposi sarcoma and primary effusion lymphoma (PEL), which
preferentially arise in HIV+ patients and lack effective treatment. Sphingosine
kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for
the conversion of proapoptotic ceramides to antiapoptotic sphingosine-1-phosphate
(S1P). We have previously demonstrated that targeting SphK2 using a novel
selective inhibitor, ABC294640, leads to the accumulation of intracellular
ceramides and induces apoptosis in KSHV-infected primary endothelial cells and
PEL tumor cells but not in uninfected cells. In this study, we found that
ABC294640 induces autophagic death instead of apoptosis in a KSHV
long-term-infected immortalized endothelial cell-line, TIVE-LTC, but not in
uninfected TIVE cells, through the upregulation of LC3B protein. Transcriptomic
analysis indicates that many genes related to cellular stress responses, cell
cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC
exposed to ABC294640. One of the candidates, Egr-1, was found to directly
regulate LC3B expression and was required for the ABC294640-induced autophagic
death. By using a Kaposi sarcoma-like nude mice model with TIVE-LTC, we found
that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in
vivo, which indicates that targeting sphingolipid metabolism, especially SphK2,
may represent a promising therapeutic strategy against KSHV-related malignancies.
Mol Cancer Ther; 16(12); 2724-34. ©2017 AACR.
<br><br>
2. Cancer Biol Ther. 2011 Mar 1;11(5):524-34. Epub 2011 Mar 1.
<br><br>
Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in
hepatocellular carcinoma xenografts.
<br><br>
Beljanski V(1), Lewis CS, Smith CD.
<br>
Author information: <br>
(1)Drug Discovery Core; Hollings Cancer Center, Medical University of South
Carolina, Charleston, USA.
<br>
The balance between the pro-apoptotic lipids ceramide and sphingosine and the
pro-survival lipid sphingosine 1-phosphate (S1P) is termed the /sphingosine
rheostat/. Two isozymes, sphingosine kinase 1 and 2 (SK1 and SK2), are
responsible for phosphorylation of pro-apoptotic sphingosine to form pro-survival
S1P. We have previously reported the antitumor properties of an SK2 selective
inhibitor, ABC294640, alone or in combination with the multikinase inhibitor
sorafenib in mouse models of kidney carcinoma and pancreatic adenocarcinoma. Here
we evaluated the combined antitumor effects of the aforementioned drug
combination in two mouse models of hepatocellular carcinoma. Although combining
the SK2 inhibitor, ABC294640, and sorafenib in vitro only afforded additive
drug-drug effects, their combined antitumor properties in the mouse model bearing
HepG2 cells mirrored effects previously observed in animals bearing kidney
carcinoma and pancreatic adenocarcinoma cells. Combining ABC294640 and sorafenib
led to a decrease in the levels of phosphorylated ERK in SK-HEP-1 cells,
indicating that the antitumor effect of this drug combination is likely mediated
through a suppression of the MAPK pathway in hepatocellular models. We also
measured levels of S1P in the plasma of mice treated with two different doses of
ABC294640 and sorafenib. We found decreases in the levels of S1P in plasma of
mice treated daily with 100 mg/kg of ABC294640 for 5 weeks, and this decrease was
not affected by co-administration of sorafenib. Taken together, these data
support combining ABC294640 and sorafenib in clinical trials in HCC patients.
Furthermore, monitoring levels of S1P may provide a pharmacodynamic marker of
ABC294640 activity.
<br>
3. J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. doi: 10.1124/jpet.109.163444. Epub
2010 Jan 8.
<br><br>
Pharmacology and antitumor activity of ABC294640, a selective inhibitor of
sphingosine kinase-2.
<br><br>
French KJ(1), Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green
CL, Keller SN, Smith CD.
<br>
Author information: <br>
(1)Apogee Biotechnology Corporation, Hummelstown, PA 17036, USA.
<br>
Sphingolipid-metabolizing enzymes control the dynamic balance of the cellular
levels of important bioactive lipids, including the apoptotic compound ceramide
and the proliferative compound sphingosine 1-phosphate (S1P). Many growth factors
and inflammatory cytokines promote the cleavage of sphingomyelin and ceramide
leading to rapid elevation of S1P levels through the action of sphingosine
kinases (SK1 and SK2). SK1 and SK2 are overexpressed in a variety of human
cancers, making these enzymes potential molecular targets for cancer therapy. We
have identified an aryladamantane compound, termed ABC294640
[3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], that
selectively inhibits SK2 activity in vitro, acting as a competitive inhibitor
with respect to sphingosine with a K(i) of 9.8 muM, and attenuates S1P formation
in intact cells. In tissue culture, ABC294640 suppresses the proliferation of a
broad panel of tumor cell lines, and inhibits tumor cell migration concomitant
with loss of microfilaments. In vivo, ABC294640 has excellent oral
bioavailability, and demonstrates a plasma clearance half-time of 4.5 h in mice.
Acute and chronic toxicology studies indicate that ABC294640 induces a transient
minor decrease in the hematocrit of rats and mice; however, this normalizes by 28
days of treatment. No other changes in hematology parameters, or gross or
microscopic tissue pathology, result from treatment with ABC294640. Oral
administration of ABC294640 to mice bearing mammary adenocarcinoma xenografts
results in dose-dependent antitumor activity associated with depletion of S1P
levels in the tumors and progressive tumor cell apoptosis. Therefore, this newly
developed SK2 inhibitor provides an orally available drug candidate for the
treatment of cancer and other diseases.
<br>
|
