Alkaloids derived from flowers of Senna spectabilis, (−)-cassine and (−)-spectaline, have antiproliferative activity on HepG2 cells for inducing cell cycle arrest in G1/S transition through ERK inactivation and downregulation of cyclin D1 expression

Toxicology in Vitro

Volume 31, March 2016, Pages 86–92

• Rodrigo Machado Pereira^a,
• Guilherme Álvaro Ferreira-Silva^a,
• Marcos Pivatto^b,
• Luciana de Ávila Santos^c,
• Vanderlan da Silva Bolzani^c,
• Daniela Aparecida Chagas de Paula^d,
• Jaqueline Carvalho de Oliveira^e,
• Cláudio Viegas Júnior^f,
• Marisa Ionta^{a, ,}

• ^a Institute of Biomedical Sciences, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, zip code 37130-000 Alfenas, MG, Brazil
• ^b Nucleus of Research in Natural Products (NuPPeN), Institute of Chemistry, Federal 'University of Uberlândia, Avenida João Naves de Ávila, 2121, zip code 38408-144 Uberlândia, MG, Brazil
• ^c Institute of Chemistry, State University of São Paulo, Rua Francisco Degni s/n, zip code 14801-970 Araraquara, SP, Brazil
• ^d Laboratory of Phytochemistry and Medicinal Chemistry (LFQM), Institute of Chemistry, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, zip code 37130-000 Alfenas, MG, Brazil
• ^e Institute of Natural Science, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, zip code 37130-000 Alfenas, MG, Brazil
• ^f Laboratory of Research on Medicinal Chemistry (PeQuiM), Institute of Chemistry, Federal University of Alfenas, Av. Jovino Fernandes Sales, 2600, zip code 37130-000 Alfenas, MG, Brazil

Received 4 September 2015, Revised 17 November 2015, Accepted 22 November 2015, Available online 23 November 2015

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Highlights

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(−)-Cassine/(−)-Spectaline alkaloid mixture inhibits cell proliferation in hepatocellular carcinoma cell line.

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Antiproliferative activity of (−)-cassine/(−)-spectaline alkaloids is associated to cell cycle arrest in G1/S transition.

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(−)-Cassine/(−)-Spectaline alkaloids are effective in modulating cyclin D expression.

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ERK activation is inhibited in HepG2 cells treated with (−)-cassine/(−)-spectaline alkaloids.

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Abstract

Cancer is one of the most critical problems of public health in the world and one of the main challenges for medicine in this century. Unfortunately, most patients are diagnosed at advanced stage, when the treatment options are palliative. Consequently, the search for novel therapeutic options is imperative. In the context, the plants represent an important source for discovering of novel compounds with pharmacological potential including antineoplastic agents. Herein, we aimed to investigate in vitro antiproliferative and cytotoxic potentials of an alkaloid mixture derived from Senna spectabilis, (−)-cassine (1) and (−)-spectaline (2). These alkaloids reduced cell viability in a concentration-dependent manner of six tumor cell lines. From initial screening, HepG2 cells were selected for further investigations. We show that alkaloids 1/2 have an important antiproliferative activity on HepG2 cells due to their ability in inducing cell cycle arrest in G1/S transition. This effect was associated to ERK inactivation and down-regulation of cyclin D1 expression. In addition, we evidenced a disruption of the microfilaments and microtubules in a consequence of the treatment. Taken together, the data showed by the first time that alkaloids 1/2 strongly inhibit cell proliferation of hepatocellular carcinoma cells. Therefore, they represent promise antitumor compounds against liver cancer and should be considered for further anticancer in vivo studies.

Keywords

• Hepatocellular carcinoma;
• Cell cycle arrest;
• (−)-Cassine;
• (−)-Spectaline;
• Piperidine alkaloids;
• Senna spectabilis

Corresponding author.

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