Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents.

Anne Cecília Nascimento Da Cruz,Antônio Rodolfo De Faria,Sylvie Piessard,Rafael Matos Ximenes,Stéphane Bach,Pascal Marchand,Marcelo Montenegro Rabello,Julianna Ferreira Cavalcanti De Albuquerque,Marcelo Zaldini Hernandes,Lucas Oliveira Da Silva,Elizabeth Fernanda Da Oliveira Borba,Dalci José Brondani,Blandine Baratte,Sandrine Ruchaud,Marc-Antoine Bazin,Teresinha Gonçalves Da Silva,Francisco Jaime Bezerra Mendonça Junior,Temístocles I´Talo De Santana

doi:10.3390/ph12040169

Abstract

Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).

Highlights

Cancer is a group of potentially fatal diseases characterized by uncontrolled growth of abnormal cells due to defects in intracellular signaling, being responsible for enormous health costs around the world [1]
Mitochondria play an essential role in the life and death of cells, as they are responsible for the energy production necessary for cell survival and regulate apoptosis
Some drugs act by inducing the loss of mitochondrial transmembrane potential leading to a process called mitochondrial depolarization, which is one of the early events in the process of cell death by apoptosis triggered by the intrinsic pathway [44]

Summary

Introduction

Cancer is a group of potentially fatal diseases characterized by uncontrolled growth of abnormal cells due to defects in intracellular signaling, being responsible for enormous health costs around the world [1]. The main therapeutic approaches used to treat cancer are surgery, radiotherapy and systemic therapy Such treatments may be used alone or in combination and the form employed depends on the type and location of the tumor, stage of the disease and conditions concerning the patient to be treated [5]. Chemotherapeutics cause the death of cells by directly interfering with the DNA or key molecules necessary for cell division [8]. As this treatment is systemic, its action is not limited to cancer cells and profound side effects occur in the hematopoietic system, in the mucous cells of the gastrointestinal tract, hair follicle and others [10]

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Conclusion