Title:L-lysine Increases the Anticancer Effect of Doxorubicin in Breast Cancer
by Inducing ROS-Dependent Autophagy
Volume: 25
Issue: 3
Author(s): Mozhgan Jahani, Reza Yarani, Davood Rezazadeh, Hadis Tahmasebi, Zohreh Hoseinkhani, Sara Kiani and Kamran Mansouri*
Affiliation:
- Department of
Molecular Medicine, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Biology
Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
Keywords:
Doxorubicin, L-lysine, autophagy, triple-negative breast cancer, oxidative stress, reactive oxygen species.
Abstract:
Background: Doxorubicin (DOX) is a chemotherapy drug that is widely used in cancer
therapy, especially in Triple-Negative Breast Cancer (TNBC) patients. Nevertheless, cytoprotective
autophagy induction by DOX limits its cytotoxic effect and drug resistance induction in patients.
Therefore, finding a new way is essential for increasing the effectiveness of this drug for
cancer treatment.
Objective: This study aimed to investigate the effect of L-lysine on DOX cytotoxicity, probably
through autophagy modulation in TNBC cell lines.
Methods: We used two TNBC cell lines, MDA-MB-231 and MDA-MB-468, with various levels
of autophagy activity. Cell viability after treatment with L-lysine alone and in combination therapy
was evaluated by MTT assay. Reactive Oxygen Species (ROS), nitric oxide (NO) concentration,
and arginase activity were assessed using flow cytometric analysis, Griess reaction, and arginase
activity assay kit, respectively. Real-time PCR and western blot analysis were used to evaluate
the L-lysine effect on the autophagy-related genes and protein expression. Cell cycle profile
and apoptotic assay were performed using flow cytometric analysis.
Results: The obtained data indicated that L-lysine in both concentrations of 24 and 32 mM increased
the autophagy flux and enhanced the DOX cytotoxicity, especially in MDA-MB-231,
which demonstrated higher autophagy activity than MDA-MB-468, by inducing ROS and NO production.
Furthermore, L-lysine induced G2/M arrest autophagy cell death, while significant apoptotic
changes were not observed.
Conclusion: These findings suggest that L-lysine can increase DOX cytotoxicity through autophagy
modulation. Thus, L-lysine, in combination with DOX, may facilitate the development of novel
adjunct therapy for cancer.
