Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs

Kabirov, Kasim K.; Kapetanović, Izet M.; Benbrook, Doris M.; Dinger, Nancy; Mankovskaya, I. N.; Zakharov, Alexander; Detrisac, Carol J.; Pereira, Marcia; Martı́n-Jiménez, Tomás; Onua, Emmanuel; Banerjee, Aryamitra; Breemen, Richard B. van; Nikolić, Dejan; Chen, Lian; Lyubimov, Alexander V.

doi:10.3109/01480545.2012.710632

Cited by 33 publications

(62 citation statements)

References 15 publications

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“…Knowledge of the mechanism can be used to select the appropriate patient population and to design improved analogs. Pre-clinical testing for our lead compound, a flexible heteroarotinoid (Flex-Het) called Sulfur Het A2 (SHetA2, NSC721689) demonstrated reasonable pharmacokinetics and lack of mutagenicity, carcinogenicity, teratogenicity and toxicity [1–5]. SHetA2 has a wide therapeutic window as indicated by the No Observed Adverse Effect Level (NOAEL) of >1,500 mg/kg/day identified in the 28 day dog toxicity model in comparison to the ability of 10 to 60 mg/kg/day to inhibit xenograft tumor growth [5–8].…”

Section: Introductionmentioning

confidence: 99%

“…Pre-clinical testing for our lead compound, a flexible heteroarotinoid (Flex-Het) called Sulfur Het A2 (SHetA2, NSC721689) demonstrated reasonable pharmacokinetics and lack of mutagenicity, carcinogenicity, teratogenicity and toxicity [1–5]. SHetA2 has a wide therapeutic window as indicated by the No Observed Adverse Effect Level (NOAEL) of >1,500 mg/kg/day identified in the 28 day dog toxicity model in comparison to the ability of 10 to 60 mg/kg/day to inhibit xenograft tumor growth [5–8]. This lack of in vivo toxicity, along with oral bioavailability and documented inhibition of colorectal tumorigenesis in the APC min/+ mouse model at 30 mg/kg given 5 days per week, make SHetA2 an ideal candidate for a cancer prevention drug [9].…”

Section: Introductionmentioning

confidence: 99%

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SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres

et al. 2013

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SummarySHetA2 is a small molecule flexible heteroarotinoid (Flex-Het) with promising cancer prevention and therapeutic activity. Extensive preclinical testing documented lack of SHetA2 toxicity at doses 25 to 150 fold above effective doses. Knowledge of the SHetA2 molecular target(s) that mediate(s) the mechanism of SHetA2 action is critical to appropriate design of clinical trials and improved analogs. The aim of this study was to develop a method to identify SHetA2 binding proteins in cancer cells. A known metabolite of SHetA2 that has a hydroxyl group available for attachment was synthesized and conjugated to a linker for attachment to a magnetic microsphere. SHetA2-conjugated magnetic microspheres and unconjugated magnetic microspheres were separately incubated with aliquots of a whole cell protein extract from the A2780 human ovarian cancer cell line. After washing away non-specifically bound proteins with the protein extraction buffer, SHetA2-binding proteins were eluted with an excess of free SHetA2. In two independent experiments, an SDS gel band of about 72 kDa was present at differential levels in wells of eluent from SHetA2-microspheres in comparison to wells of eluent from unconjugated microspheres. Mass spectrometry analysis of the bands (QStar) and straight eluents (Orbitrap) identified mortalin (HSPA9) to be present in the eluent from SHetA2-microspheres and not in eluent from unconjugated microspheres. Co-immunoprecipitation experiments demonstrated that SHetA2 interfered with mortalin binding to p53 and p66 Src homologous-collagen homologue (p66shc) inside cancer cells. Mortalin and SHetA2 conflictingly regulate the same molecules involved in mitochondria-mediated intrinsic apoptosis. The results validate the power of this protocol for revealing drug targets.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-013-0041-x) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres

et al. 2013

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“…Based on pre-clinical data, the small molecule compounds called Flexible Heteroarotinoids (Flex-Hets, Fig. 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).…”

Section: Introductionmentioning

confidence: 99%

“…The National Cancer Institute (NCI) Rapid Access to Intervention Development (RAID) and Rapid Access to Preventive Intervention Development (RAPID) programs completed the preclinical testing needed for an Investigational New Drug (IND) application to the US Food and Drug Administration (FDA) for initiation of SHetA2 clinical trials (5, 11, 17, 18). The ID given to SHetA2 in these studies is NSC721689.…”

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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“…Retinoids and RRMs have demonstrated some activity in melanoma and ovarian cancer [5,60,61]. The efficacy and lack of toxicity prompted pre-clinical development of SHetA2 in the US National Cancer Institute (NCI) RAID and RAPID programs, which demonstrated lack toxicity of SHetA2 at doses 50 fold above the dose required to reduce xenograft tumor growth [62][63][64][65].…”

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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Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs

Cited by 33 publications

References 15 publications

SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres

SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres

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

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