PhD Scientific Days 2025

EUniWell I.

New Insights into the Anticancer Effects and Toxicogenomic Safety of Two β-Lapachone Derivatives

Name of the presenter

de Lima José Rivaldo

Institute/workplace of the presenter

Federal University of Pernambuco (Brazil)

Authors

Jose Rivaldo de Lima^1,2, Alexandre José Da Silva Góes¹, Elizabeth Fernanda De Oliveira Borba¹, Meykson Alexandre da Silva (2),Rodrigo Ribeiro Alves Caiana¹, Maria do Desterro Rodrigues¹, Mariza Severina De Lima Silva¹, Cristiano Aparecido Chagas³, Blandine Baratte^4,5, Thomas Robert^4,6, Stéphane Bach^4,6, Isabelle Ourliac-Garnier², Pascal Marchand², Teresinha Gonçalves Da Silva⁷

1: Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife, Brazil
2: Cibles et Médicaments des Infections et de L’immunité, IICiMed, UR 1155, Nantes Université, France
3: Centro Acadêmico de Vitória, Universidade Federal de Pernambuco, Vitória de Santo Antão, Brazil
4: Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, Sorbonne Université, Roscoff, France
5: Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, Sorbonne Université, F-29680 Roscoff, France
6: Plateforme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, Sorbonne Université, Roscoff, France
7: Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife 50670-420, Brazil

Text of the abstract

Introduction: β-Lapachone (β-lap), an o-naphthoquinone, exhibits significant antitumor properties, though its clinical applicability is constrained by limited solubility and toxicity concerns. Modified thiosemicarbazone derivatives of β-lap (BV3 and BV5) have shown improved selectivity and enhanced anticancer activity in leukemia models. Objectives: This study aimed to explore the therapeutic effects of BV3 and BV5 in solid tumors, elucidate their mechanisms of inducing tumor cell death, evaluate their protein kinase inhibitory potential, and assess their toxicogenetic safety profiles. Results: The cytotoxic potential of BV3 and BV5 was investigated across various cancer cell lines and a non-tumorigenic control cell line. HeLa cells (human cervical adenocarcinoma) displayed the highest sensitivity and were selected for mechanistic studies of cell death using flow cytometry. Protein kinase inhibition was analyzed both in vitro and through computational modeling. Genotoxicity assays were also performed to determine toxicogenetic safety. Treatment with BV3 and BV5 led to a significant suppression of cancer cell growth after 72 hours, with IC₅₀ values ranging from 2.8 to 36.9 µM. BV3 demonstrated a higher selectivity index (15.6) compared to β-lap (1.9) in HeLa cells. Morphological assessments and flow cytometric analysis indicated that both compounds induced apoptotic and/or necrotic processes in HeLa cells. BV3 and BV5 also exhibited pronounced inhibitory effects on JAK3 and GSK3β protein kinases, as confirmed by in vitro assays and in silico studies. Genotoxicity evaluations revealed an overall favorable safety profile, although BV5 displayed potential genotoxic effects at elevated concentrations.Conclusions: The results support the anticancer potential of BV3 and BV5 in solid tumor models, emphasizing their selectivity and protein kinase-mediated mechanisms of action, along with an acceptable safety margin.

Public funding: Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.