Combinational therapy of all-trans retinoic acid (ATRA) and sphingomyelin induces apoptosis and cell cycle arrest in B16F10 melanoma cancer cell

Authors

ZEYNEP İŞLEK KÖKLÜFollow
ELİF LİDYA ŞANVERDİFollow
BAŞAK KARADAĞFollow
MEHMET HİKMET ÜÇIŞIKFollow
EZGİ TAŞKANFollow
FİKRETTİN ŞAHİNFollow

Abstract

Background: Melanoma arises from the uncontrolled multiplication of melanocytes, posing an escalating global health concern. Despite early detection and surgical removal being crucial, metastatic melanoma poses treatment challenges, with limited options like chemotherapy and immunotherapy. All-trans retinoic acid (ATRA), a natural metabolite of vitamin A, has shown promise in melanoma treatment by inducing differentiation, apoptosis, growth arrest, and immune modulation. However, ATRA treatment alone can lead to resistance and relapse. Sphingomyelin (SM) also plays a role in inhibiting melanoma progression by apoptotic cell death.Objective: This study investigated combinational anticancer effects of ATRA and SM on in vitro B16F10 melanoma cells.Method: The combinational anticancer effects were evaluated based on viability, apoptotic death, cell cycle progression, and caspase, Bax, Anti-Programmed Cell Death Ligand 1 (Anti-PD-L1), and Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) gene expressions; whereas the safety properties were tested on RAW264.7 macrophages. The datasets underwent initial ordinary one-way analysis of variance (ANOVA), followed by two-way ANOVA, and were subsequently scrutinized by Tukey's multiple comparison test.Results: The combination of 123 µM ATRA and 136 µM SM significantly reduced B16F10 proliferation by 50%, induced 53.91% apoptosis within 48 hours, and caused G2/M phase-cell cycle arrest. Combinational therapy increased Cas 3 and Bax gene expressions by 2-fold and 5-fold, respectively, while enhancing CDKN2A expression by 13-fold and suppressing Programmed Death Ligand 1 expression by 0.5-fold.Conclusion: The ATRA and SM combination could be a promising therapeutic approach for melanoma, potentially improving efficacy while relatively reducing toxicity to healthy cells.

Author ORCID Identifier

ZEYNEP İŞLEK KÖKLÜ: 0000-0003-4789-9095

ELİF LİDYA ŞANVERDİ: 0009-0001-4274-3158

BAŞAK KARADAĞ: 0009-0009-3530-565X

MEHMET ÜÇIŞIK: 0000-0001-9434-3861

EZGİ TAŞKAN: 0000-0002-9683-2906

FİKRETTİN ŞAHİN: 0000-0003-1503-5567

DOI

10.55730/1300-0152.2715

Keywords

All-trans retinoic acid, sphingomyelin, melanoma, combinational chemotherapy, apoptosis, cell cycle arrest

First Page

401

Last Page

413

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

İŞLEK KÖKLÜ, ZEYNEP; ŞANVERDİ, ELİF LİDYA; KARADAĞ, BAŞAK; ÜÇIŞIK, MEHMET HİKMET; TAŞKAN, EZGİ; and ŞAHİN, FİKRETTİN (2024) "Combinational therapy of all-trans retinoic acid (ATRA) and sphingomyelin induces apoptosis and cell cycle arrest in B16F10 melanoma cancer cell," Turkish Journal of Biology: Vol. 48: No. 6, Article 6. https://doi.org/10.55730/1300-0152.2715
Available at: https://journals.tubitak.gov.tr/biology/vol48/iss6/6