Flexible heteroarotinoid (Flex-Het) SHetA2 inhibits angiogenesis in vitro and in vivo

Myers, Tashanna; Chengedza, Shylet; Lightfoot, Stan; Pan, Yanfang; Dedmond, Daynelle; Cole, Lauren; Tang, Yuhong; Benbrook, Doris M.

doi:10.1007/s10637-008-9175-7

Cited by 32 publications

(31 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SHetA2 offers promise in this regard in that it has not exhibited toxicities in multiple animal models, including models of ovarian cancer xenograft growth, skin irritancy, and teratogenicity (22,26,27). Further evidence for SHetA2 chemoprevention activity includes the reversal of carcinogen-induced transformation in an in vitro organotypic model and in vivo inhibition of angiogenesis and xenograft growth (23,27). The demonstration in this study that SHetA2 induces G 1 arrest in all cell lines tested regardless of the status of p53 suggests that it will be effective against a broad spectrum of tumor types, including tumors that have lost p53 function.…”

Section: Discussionmentioning

confidence: 99%

“…Flexible heteroarotinoids (Flex-Het) are small molecules that offer promise in ovarian cancer because they induce differentiation, apoptosis, and growth inhibition without evidence of toxicity (22)(23)(24)(25)(26)(27). The lead Flex-Het, SHetA2, is currently in preclinical development and was chosen because it exhibited the greatest efficacy in inducing apoptosis in multiple cancer cell lines without killing the normal cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells

Masamha¹,

2009

View full text Add to dashboard Cite

D-and E-type cyclins mediate G 1 -S phase cell cycle progression through activation of specific cyclin-dependent kinases (cdk) that phosphorylate the retinoblastoma protein (pRb), thereby alleviating repression of E2F-DP transactivation of S-phase genes. Cyclin D1 is often overexpressed in a variety of cancers and is associated with tumorigenesis and metastasis. Loss of cyclin D can cause G 1 arrest in some cells, but in other cellular contexts, the downstream cyclin E protein can substitute for cyclin D and facilitate G 1 -S progression. The objective of this study was to determine if a flexible heteroarotinoid anticancer compound, SHetA2, regulates cell cycle proteins and cell cycle progression in ovarian cancer cells. SHetA2 induced cyclin D1 phosphorylation, ubiquitination, and proteasomal degradation, causing G 1 arrest in ovarian cancer cells despite continued cyclin E2 expression and independently of p53 and glycogen synthase kinase-3B. Cyclin D1 loss inhibited pRb S780 phosphorylation by cyclin D1-cdk4/6 and released p21 from cyclin D1-cdk4/6-p21 protein complexes to form cyclin E2-cdk2-p21 complexes, which repressed phosphorylation of pRb S612 by cyclin E2-cdk2 and ultimately E2F-DP transcriptional activity. G 1 arrest was prevented by overexpression or preventing degradation of cyclin D1 but not by restoration of pRb S612 phosphorylation through p21 knockdown. In conclusion, we show that loss of cyclin D1 in ovarian cancer cells treated with SHetA2 is sufficient to induce G 1 cell cycle arrest and this strategy is not impeded by the presence of cyclin E2. Therefore, cyclin D1 is a sufficient therapeutic target in ovarian cancer cells. [Cancer Res 2009;69(16):6565-72]

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells

Masamha¹,

2009

View full text Add to dashboard Cite

show abstract

“…1A) have the potential to meet these criteria (1–18). In vitro , Flex-Hets regulate growth, differentiation and apoptosis in cancer cells, while the effects on normal cells are limited to growth inhibition (1, 3, 6, 7, 12–15). In organotypic culture, they reverse the cancerous phenotype of ovarian and kidney cancer cell lines and primary cultures (1, 13).…”

Section: Introductionmentioning

confidence: 99%

“…SHetA2 prevented carcinogen-induced transformation of human endometrial organotypic cultures (8). In vivo , the lead Flex-Het, Sulfur Heteroarotinoid A2 (SHetA2), inhibited xenograft tumor angiogenesis and growth without evidence of gross toxicity (4, 12, 13). …”

Section: Introductionmentioning

confidence: 99%

Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCmin/+ Mice By SHetA2 (NSC721689) without Toxicity

Benbrook

Guruswamy

Wang

et al. 2013

Cancer Prevention Research

View full text Add to dashboard Cite

The occurrence of intestinal polyps in people at high risk for developing colorectal cancer provides an opportunity to test the efficacy of chemoprevention agents. In this situation of treating otherwise healthy people, the potential for toxicity must be minimal. The small molecule flexible heteroarotinoid (Flex-Het), called SHetA2, has chemoprevention activity in organotypic cultures in vitro and lack of toxicity at doses capable of inhibiting xenograft tumor growth in vivo. The objective of this study was to evaluate SHetA2 chemoprevention activity and toxicity in the APCMin/+ murine model. Oral administration of SHetA2 at 30 and 60 mg/kg five days per week for 12 weeks significantly reduced development of intestinal polyps by 40 to 60% depending on the dose and sex of the treatment group. Immunohistochemical and Western blot analysis of polyps demonstrated reduced levels of cyclin D1 and proliferating cell nuclear antigen (PCNA) in both SHetA2 treatment groups. Western blot analysis also demonstrated SHetA2 induction of E-cadherin, Bax and caspase 3 cleavage along with reduction in Bcl-2, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), consistent with SHetA2 regulation of apoptosis, inflammation and angiogenesis. Neither dose caused weight loss nor gross toxicity in APCMin/+ or wild type littermates. Magnetic resonance imaging (MRI) of cardiac function showed no evidence of SHetA2 toxicity. SHetA2 did not alter left ventricular wall thickness. In summary, SHetA2 exerts chemoprevention activity without overt or cardiac toxicity in the APCMin/+ model. SHetA2 modulation of biomarkers in colon polyps identifies potential pharmacodynamic endpoints for SHetA2 clinical trials.

show abstract

“…The ability of imiquimod and SHetA2 to inhibit endothelial tube formation increases the potential of these compounds to be effective against cancer through their alterations of the tumor microenvironment. The mechanism of SHetA2 inhibition of angiogenesis involves regulation of both cancer and endothelial cells [73]. The direct effects on cancer cells involve inhibition of angiogenic cytokine secretion, while the direct effects on endothelial cells involve inhibition of cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

Naylor¹,

Thompson²,

Lightfoot³

et al. 2013

JCT

Self Cite

View full text Add to dashboard Cite

New strategies are needed to treat cancers that do not respond to chemotherapy or resist chemotherapy after responding initially. The objective of this study was to evaluate non-cytotoxic drugs against two of these cancers, melanoma and ovarian cancer. Imiquimod is an immune stimulant that induces apoptosis in cancer cells. Flexible-Heteroarotinoids (Flex-Hets) are small molecules that regulate growth, differentiation and apoptosis in cancer cells with reduced effects on normal cells. Both imiquimod and SHetA2 inhibited growth and induced apoptosis in the B16 melanoma cell line and cisplatin-sensitive A2780 and cisplatin-resistant OVCAR-3 ovarian cancer cell lines. The growth inhibition was additive in A2780 and B16, and synergistic in OVCAR-3. Both compounds inhibited endothelial tube branching in vitro and exerted an additive effect when combined. Various combinations of imiquimod and SHetA2 did not cause significant differences in the overall survival in the syngeneic B16 murine melanoma model. SHetA2 induced complete tumor regression and a melanoma-free natural life-span in two mice. These cures occurred in one of ten mice treated with oral SHetA2 and one of ten mice intratumorally-injected with SHetA2. Exploratory modeling of the distribution of survival times suggested that the two surviving mice represent rare events. Histologic evaluation of the tumors revealed that imiquimod induced necrosis, SHetA2 induced differentiated architecture and increased cytoplasm, both agents reduced mitotic indices and angiogenesis and neither agent counteracted the effects of the other. No overt toxicities were observed. In conclusion, imiquimod and SHetA2 exhibit complementary anti-cancer activity in vitro and SHetA2 has promise as a single agent.

show abstract

Flexible heteroarotinoid (Flex-Het) SHetA2 inhibits angiogenesis in vitro and in vivo

Cited by 32 publications

References 30 publications

Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells

Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells

Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCmin/+ Mice By SHetA2 (NSC721689) without Toxicity

Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

Contact Info

Product

Resources

About