Levoleucovorin inhibits LOXL2 (lysyl oxidase like-2) to control breast cancer proliferation: a repurposing approach

Abstract

Lysyl oxidase like-2 (LOXL2) belongs to copper dependent amine oxidase from the lysyl oxidase family and is associated with breast cancer metastasis This study used multi-stage computational screening and in vitro validations to repurpose FDA approved drugs targeting LOXL2 to control breast cancer progression.Molecular modeling techniques and high-throughput virtual-screening technique was employed to screen FDA-approved drug library for its avid binding to LOXL2.hLOXL2, MDA-MB231 and MCF 7 cells were used for in vitro.Collectively, this repurposing study identified levoleucovorin to bind the active site of LOXL2 protein to inhibit its activity. Further validation of levoleucovorin against LOXL2 activity is warranted toward repurposing levoleucovorin as a therapeutic agent for treating breast cancer patients. validations.Computational modeling of LOXL2 identified putative druggable region at the active site of LOXL2 protein. High-throughput virtual screening predicted levoleucovorin as a best lead drug candidate to have a favorable binding affinity for LOXL2 at its active site. Molecular dynamic simulation predicts levoleucovorin to bind stably and avidly to LOXL2 with favorable interactions. In vitro validations show levoleucovorin significantly inhibited hLOXL2 with and IC50 value of 68.81 μM. Levoleucovorin controlled cell proliferations in MDM-MB 231 and MCF-7 cells with GI50 values of 55.91 μM and 79.20 μM respectively. Further, a dose dependent inhibition of cancer cell migration was noted along with apoptosis induction in these cells with levoleucovorin treatment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Breast cancer
• computational modeling
• levoleucovorin
• LOXL2
• virtual drug discovery

Acknowledgements

Authors express their gratitude to SMARTBIO LABS, Chennai-78, Tamil Nadu, India and SiBI-OLEAD, Little Rock, Arkansas, USA for the help rendered in this study.

Author contributions

Hemali Deshpande – funding acquisition, experimental, plan execution, data curing manuscript drafting, manuscript finalization and communication.

Data availability statement

All data used in manuscript and is available with corresponding author upon reasonable request for non-commercial purposes.

Disclosure statement

The author of this manuscript declares there in no any conflict of interest related to the study.

Additional information

Funding

The author thanks Deanship of Scientific Research, King Khalid University, Abha, Saudi Arabia for their support through research grant # GRP/216/43.