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Invest New Drugs. 2019 Sep 6. doi: 10.1007/s10637-019-00849-6. [Epub ahead of print]

A new series of acetohydroxamates shows in vitro and in vivo anticancer activity against melanoma.

Author information

1
Center of Innovation and Preclinical Studies (CIEnP), Av. Luiz Boiteux Piazza, 1302, Cachoeira do Bom Jesus, Florianópolis, SC, 88056-000, Brazil.
2
Department of Pharmacology, Biological Sciences Centre, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
3
Department of Chemistry, North Caucasus Federal University, 1a Pushkin St, Stavropol, Russian Federation.
4
Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, USA.
5
Center of Innovation and Preclinical Studies (CIEnP), Av. Luiz Boiteux Piazza, 1302, Cachoeira do Bom Jesus, Florianópolis, SC, 88056-000, Brazil. joao.calixto@cienp.org.br.
6
Department of Pharmacology, Biological Sciences Centre, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. joao.calixto@cienp.org.br.

Abstract

Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development.

KEYWORDS:

Acetohydroxamate; Cancer; Drug development; Melanoma

PMID:
31493129
DOI:
10.1007/s10637-019-00849-6

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