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Cativic acid-caffeic acid hybrid exerts cytotoxic effects and induces apoptotic death in human neuroblastoma cells

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Abstract

The development of hybrids from natural products is a promising strategy for drug discovery. In cancer therapy, there is a need to discover novel agents that can induce apoptosis in cancer cells. To contribute to this field of interest, we investigated the effect of a synthetic hybrid from cativic acid and caffeic acid (5) on viability, proliferation, and apoptosis in human neuroblastoma cells (IMR-32). Three hybrids were prepared via Mitsunobu esterification from 17-hydroxycativic acid (1) and natural phenols. Cell viability was analyzed by MTT assay. SYTOX green and LDH leakage were used to determine the cytotoxic effect. Caspase-3 activity, cell cycle phases, and proliferation were analyzed in order to characterize the biological effects of hybrid 5. The mitogen-activated protein kinase (MAPK) status was evaluated for elucidating the potential mechanisms involved in hybrid 5 effect. Hybrid 5 reduced the viability of IMR-32 cells in a time- and concentration-dependent manner (IC50 = 18.0 ± 1.3 μM) as a result of its antiproliferative effect through changes in the cell cycle distribution and induction of apoptosis associated with activation of caspase-3. Exposure to 5 triggered ERK1/2 activation and nuclear translocation. Hybrid 5 also promoted an increase in nuclear localization of the transcription factor c-Jun. Inhibition of ERK1/2 and JNK potentiated 5-induced inhibition of IMR-32 viability. Hybrid 5 displays cell growth inhibition by promoting cell cycle arrest and apoptosis, through ERK1/2 and JNK participation.

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Acknowledgements

The authors wish to thank Wiener Laboratories for kindly providing LDH kits. They also gratefully acknowledge Dr. Maria Marta Facchinetti and Dr. Alejandro Curino for kindly providing HCT-116 and MDA-MB-231 cancer cell lines and Dr. I. Luthy for a sample of paclitaxel. NPA is a post-doctoral fellow of CONICET. GAS and APM are research members of CONICET. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of this manuscript.

Funding

This work was supported by the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) (PICT-2013-0987 and PICT-2011-0765), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) (PIP1122009010068 and PIP11220100100392), and the Universidad Nacional del Sur (UNS) (PGI24B179 and PGI24Q071) to GAS and to APM, respectively.

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Authors and Affiliations

  1. Instituto de Investigaciones Bioquímicas de Bahía Blanca, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Camino La Carrindanga km 7, 8000, Bahía Blanca, Argentina

    Natalia P. Alza & Gabriela A. Salvador

  2. Instituto de Química del Sur, Departamento de Química, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Alem 1253, 8000, Bahía Blanca, Argentina

    Natalia P. Alza & Ana P. Murray

Authors
  1. Natalia P. Alza
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  2. Ana P. Murray
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  3. Gabriela A. Salvador
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Correspondence to Gabriela A. Salvador.

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NMR and HR-MS data of compounds 2–5 (DOCX 2154 kb)

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Alza, N.P., Murray, A.P. & Salvador, G.A. Cativic acid-caffeic acid hybrid exerts cytotoxic effects and induces apoptotic death in human neuroblastoma cells. Naunyn-Schmiedeberg's Arch Pharmacol 390, 1229–1238 (2017). https://doi.org/10.1007/s00210-017-1421-0

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  • DOI: https://doi.org/10.1007/s00210-017-1421-0

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