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

  • Gabriela C. Segat
  • Camila G. Moreira
  • Evelyn C. Santos
  • Melina Heller
  • Raquel C. Schwanke
  • Alexander V. Aksenov
  • Nicolai A. Aksenov
  • Dmitrii A. Aksenov
  • Alexander Kornienko
  • Rodrigo Marcon
  • João B. CalixtoEmail author
PRECLINICAL STUDIES

Summary

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 Drug development Cancer Melanoma 

Abbreviations

ATCC

American Type Culture Collection

CMCiPS

Cardiomyocytes derived from induced pluripotent stem cells

FDA

Food and Drug Administration

GI50

Growth inhibition 50%

HDAC

Histone deacetylase

MMP

Mitochondrial membrane potential

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NHDF

Non-tumoural human dermal fibroblasts

NHLF

Non-tumoural human lung fibroblasts

SrB

Sulphorhodamine B

TCA

Trichloroacetic acid

TGI

Total growth inhibition

UPLC-MS/MS

Ultra-performance liquid chromatography-tandem mass spectrometry

Notes

Acknowledgements

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Instituto Nacional de Ciência e Tecnologia (INCT-INOVAMED), Fundação de Apoio à Pesquisa de Santa Catarina (FAPESC), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). The authors gratefully thank Edir Rezende and Ana Caroline Luz Machado for their technical support. Financial support from the Russian Science Foundation (Grant #18-13-00238) is gratefully acknowledged.

Author’s contributions

G.C.S., C.G.M., E.C.S., M.H., R.C.S., A.K., R.M. and J.B.C. contributed to the study design. G.C.S., C.G.M., E.C.S., M.H., R.C.S. and R.M. conducted experiments. G.C.S., C.G.M., E.C.S., M.H. and R.C.S. performed the analysis of the data. A.V.A, N.A.A, D.A.A and A.K. contributed to the design and synthesis of the compounds. G.C.S., C.G.M., E.C.S., R.C.S., A.K., R.M. and J.B.C. contributed to the writing of the manuscript.

Funding

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Instituto Nacional de Ciência e Tecnologia (INCT-INOVAMED), Fundação de Apoio à Pesquisa de Santa Catarina (FAPESC), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Financial support from the Russian Science Foundation (Grant #18–13-00238) is gratefully acknowledged.

Compliance with ethical standards

Conflict of interest

Gabriela C Segat declares that she has no conflict of interest. Camila G Moreira declares that she has no conflict of interest. Evelyn C Santos declares that she has no conflict of interest. Melina Heller declares that she has no conflict of interest. Raquel C Schwanke declares that she has no conflict of interest. Alexander V Aksenov declares that he has no conflict of interest. Nicolai A Aksenov declares that he has no conflict of interest. Dmitrii A Aksenov declares that he has no conflict of interest. Alexander Kornienko declares that he has no conflict of interest. Rodrigo Marcon declares that he has no conflict of interest. João B Calixto declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Informed consent

For this type of study, formal consent was not required.

Supplementary material

10637_2019_849_MOESM1_ESM.pdf (499 kb)
ESM 1 (PDF 499 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Gabriela C. Segat
    • 1
    • 2
  • Camila G. Moreira
    • 1
  • Evelyn C. Santos
    • 1
  • Melina Heller
    • 1
  • Raquel C. Schwanke
    • 1
  • Alexander V. Aksenov
    • 3
  • Nicolai A. Aksenov
    • 3
  • Dmitrii A. Aksenov
    • 3
  • Alexander Kornienko
    • 3
    • 4
  • Rodrigo Marcon
    • 1
  • João B. Calixto
    • 1
    • 2
    Email author
  1. 1.Center of Innovation and Preclinical Studies (CIEnP)FlorianópolisBrazil
  2. 2.Department of Pharmacology, Biological Sciences CentreUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  3. 3.Department of ChemistryNorth Caucasus Federal UniversityStavropolRussian Federation
  4. 4.Department of Chemistry and BiochemistryTexas State UniversitySan MarcosUSA

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