Pharmacological and Toxicological Properties of Arotinoids SMR-2 and SMR-6 in Mice

Lindamood, Charles; COPE, FREDERICK O.; Dillehay, Dirck L.; EVERSON, MICHAEL P.; Giles, Herschell D.; Lamon, E W; McCarthy, Dennis J.; SARTIN, JAMES L.; Hill, Donald L.

doi:10.1093/toxsci/14.1.15

Cited by 10 publications

(13 citation statements)

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“…Early efforts to improve the therapeutic ratio involved constraining the RA double-bonds, by inclusion in an aromatic ring of chemical structures called arotinoids. The first arotinoid evaluated, TTNPB, was 10-fold more potent than RA in biological assays of efficacy, but considerably more toxic [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

et al. 2005

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The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.

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Section: Introductionmentioning

confidence: 99%

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

et al. 2005

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“…The pathologic features manifested by these necrotic spleens are a hallmark of a severe infection by MCMV. It is noteworthy that ATRAtreated uninfected mice have spleens larger than those of untreated control mice due to increased hematopoiesis in the spleen (32). These results show that ATRA-treated MCMVinfected animals exhibit greater virus-induced spleen damage than do untreated mice.…”

Section: Resultsmentioning

confidence: 77%

Ligand Induction of Retinoic Acid Receptors Alters an Acute Infection by Murine Cytomegalovirus

Angulo

Chandraratna

LeBlanc

et al. 1998

J Virol

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Here we report that administration of retinoids can alter the outcome of an acute murine cytomegalovirus (MCMV) infection. We show that a crucial viral control element, the major immediate-early enhancer, can be activated by retinoic acid (RA) via multiple RA-responsive elements (DR2) that bind retinoid X receptor-retinoic acid receptor (RAR) heterodimers with apparent dissociation constants ranging from 15 to 33 nM. Viral growth is dramatically increased upon RA treatment of infected tissue culture cells. Using synthetic retinoid receptor-specific agonists and antagonists, we provide evidence that RAR activation in cells is required for mediating the response of MCMV to RA. Oral administration of RA to infected immunocompetent mice selectively exacerbates an infection by MCMV, while cotreatment with an RAR antagonist protects against the adverse effects of RA on MCMV infection. In conclusion, these chemical genetic experiments provide evidence that an RAR-mediated pathway can modulate in vitro and in vivo infections by MCMV.

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“…Each group consisted of 3 mice. Their body weight kinetics (loss in body weight, a clinical sign of toxicity) was observed during the 14 days of dosing following established procedures (Lindamood et al, 1990;Lindamood et al, 1987). Changes in body weight were scored on a scale of 0-4 as follows: (1) Weight loss: (10 g = 4, 7-9 g = 3, 4-6 g = 2, 1-3 g = 1; severe = 3, moderate = 2, slight = 1, none = 0) (Bollag, 1975).…”

Section: In Vivo Anti-tumor Studies In Tnbc Patientmentioning

confidence: 99%

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

Ramalingam

Gediya

et al. 2018

Preprint

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Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC. Keywords:Breast cancer / metastasis / Mnk1/2 degraders / Mnk/eIF4E/mTORC1 / TNBC.

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Pharmacological and Toxicological Properties of Arotinoids SMR-2 and SMR-6 in Mice

Cited by 10 publications

References 0 publications

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

Ligand Induction of Retinoic Acid Receptors Alters an Acute Infection by Murine Cytomegalovirus

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

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