Heteroarotinoids with Anti-Cancer Activity Against Ovarian Cancer Cells

Le, Thanh C.; Berlin, K. Darrell; Benson, Stacy D.; Eastman, Margaret A.; Bell-Eunice, Gianna; Nelson, Anna C.; Benbrook, Doris M.

doi:10.2174/1874104500701010011

Cited by 14 publications

(8 citation statements)

References 34 publications

(51 reference statements)

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“…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%

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

Benbrook

Guruswamy

Wang

et al. 2013

Cancer Prevention Research

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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.

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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

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“…It suggested that the urea derivatives may be more active than its thiourea counterpart. This observation is also supported by their in vitro growth inhibition activities where the urea derivative, SHetC2 (17), demonstrated to be slightly more potent (EC 50 = 1.02 μM) than its thiourea counterpart, SHetA2 (16) (EC 50 = 1.72 μM) [41].…”

Section: Three-atom Linkersmentioning

confidence: 63%

“…SAR studies have identified structures containing six-membered ring (Figure 1, 7a, 7b) tend to confer increased RARβ selectivity over five-membered ring systems (Figure 1, 12a, 12b), while sulfur heteroatom confers a greater RARγ selectivity over oxygen atom [19]. The thiochroman ring system is flexible and has been shown to induce apoptosis to a greater extent than a rigid planar quinoline unit [41]. These findings highlight the important role played by the thiochroman ring in enhancing the activity of Flex-Hets.…”

Section: Thiochroman Ringsmentioning

confidence: 99%

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SHetA2, a New Cancer-Preventive Drug Candidate

Liu¹,

Zhou²,

Lo³

et al. 2016

Anti-Cancer Drugs - Nature, Synthesis and Cell

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SHetA2 (NSC 721689) is a novel synthetic flexible heteroarotinoid that has promising cancer-preventive activity, and has exhibited growth inhibition on 60 cancer cell lines in vitro, along with ovarian, lung, and kidney cancers in vivo. It binds and interferes with the function of a molecular chaperone, mortalin, leading to mitochondrial swelling and mitophagy that induce apoptosis in cancer cells without harming normal cells. It showed minimal toxicity in preclinical studies and thus is now in Phase-0 clinical trial. This chapter summarizes its evolution, synthesis, structure-activity relationship, mechanism of action, pharmacokinetics, and potential clinical applications in last 12 years. It also provides insights into designing more potent and safer SHetA2 analogs for future cancer-preventive drug development.

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“…These flexible Hets (Flex-Hets) are potent inducers of apoptosis in vitro and in vivo, while not harming normal cells or tissues [50][51][52][53][54][55][56]. The lead Flex-Het, SHetA2, inhibited growth of ovarian cancer xenografts without producing evidence of in vivo toxicity, skin irritancy, or teratogenicity [51,57].…”

Section: Introductionmentioning

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

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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.

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Heteroarotinoids with Anti-Cancer Activity Against Ovarian Cancer Cells

Cited by 14 publications

References 34 publications

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

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

SHetA2, a New Cancer-Preventive Drug Candidate

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

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