J Appl Biomed 21:218-227, 2023 | DOI: 10.32725/jab.2023.019

Homospisulosine induced apoptosis in cervical carcinoma cells is associated with phosphorylation of Bcl-2 and up-regulation of p27/Kip1

Martina Bago Pilátová^{1, a}, Natália Nosálová¹, Gabriela Očkajáková¹, Martin Kello^{1, *}, Klaudia Kotorová¹, Peter Takáč², Peter Petik³, Peter Bohuš³, Kvetoslava Stanková⁴, Miroslava Martinková⁴, Roman Mezencev^{5, b}

¹ Pavol Jozef Šafárik University, Faculty of Medicine, Department of Pharmacology, Košice, Slovak Republic

² University of Veterinary Medicine and Pharmacy, Department of Pharmacology and Toxicology, Košice, Slovak Republic

³ Pavol Jozef Šafárik University, Faculty of Medicine, Department of Pathology, Košice, Slovak Republic

⁴ Pavol Jozef Šafárik University, Faculty of Science, Department of Organic Chemistry, Institute of Chemical Sciences, Košice, Slovak Republic

⁵ Georgia Institute of Technology, School of Biological Sciences, Atlanta, GA, USA

Spisulosine (1-deoxysphinganine) is a sphingoid amino alcohol isolated from the sea clams that showed potent antiproliferative activity against a broad spectrum of solid tumors but failed in clinical trials due to neurotoxicity. However, its structural similarity to other bioactive sphingoids, interesting mode of action, and appreciable potency against cancer cells make it a suitable lead for future anticancer drug development. The present study was conducted to elucidate mechanisms of the antiproliferative/cytotoxic effects of newly synthesized spisulosine analog homospisulosine (KP7). The evaluation was performed on cervical carcinoma cells, representing an in vitro model of one of the most common cancer types and a significant worldwide cause of women's cancer mortality. Treatment with homospisulosine (2.0 μM) for 24, 48, and 72 h significantly inhibited the growth of HeLa cells in vitro and induced apoptosis detectable by DNA fragmentation, externalization of phosphatidylserine, dissipation of mitochondrial membrane potential, activation of caspase-3 and cleavage of PARP. In addition, treating HeLa cells with spisulosine increased p27 and Bcl-2 on protein levels and phosphorylation of Bcl-2 on Ser70 residue. These results support the potential for spisulosine analogs represented here by homospisulosine for future therapeutic development.

Keywords: Apoptosis; Cancer; Ceramide; Homospisulosine; Marine; Sphingoid bases; Sphingosine-1-phosphate; Spisulosine

Grants and funding:

This research was funded by the Slovak Grant Agency for Science VEGA No 1/0278/23, VEGA No 1/0539/21 and VEGA No 1/0653/19. This publication is also the result of the project: “Open scientific community for modern interdisciplinary research in medicine (OPENMED)”, ITMS2014+: 313011V455, supported by the Operational Programme Integrated Infrastructure, funded by the ERDF.

Conflicts of interest:

The authors have no conflict of interest to declare.

Received: May 11, 2023; Revised: August 30, 2023; Accepted: November 28, 2023; Prepublished online: November 28, 2023; Published: December 18, 2023  Show citation