Open Access

ARTICLE

LA-D-B1, a novel Abemaciclib derivative, exerts anti-breast cancer effects through CDK4/6

by LING MA^1,#, ZIRUI JIANG^1,#, XIAO HOU¹, YUTING XU¹, ZIYUN CHEN¹, SIYI ZHANG¹, HANXUE LI¹, SHAOJIE MA¹, GENG ZHANG², XIUJUN WANG^1,*, JING JI^1,*

1 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222000, China
2 School of Medicine, Xiamen University, Xiamen, 361102, China

* Corresponding Authors: XIUJUN WANG. Email: ; JING JI. Email:
# Ling Ma and Zirui Jiang are co-first authors and contributed equally to this paper

(This article belongs to the Special Issue: Navigating the Interplay of Cancer, Autophagy, ER Stress, Cell Cycle and Apoptosis: Mechanisms, Therapies, and Future Directions)

BIOCELL 2024, 48(5), 847-860. https://doi.org/10.32604/biocell.2024.050868

Received 20 February 2024; Accepted 11 March 2024; Issue published 06 May 2024

Abstract

Background: Regulatory proteins involved in human cellular division and proliferation, cyclin-dependent kinases 4 and 6 (CDK4/6) are overexpressed in numerous cancers, including triple-negative breast cancer (TNBC). TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis, and has a single treatment method. As one of the CDK4/6 inhibitors, abemaciclib can effectively inhibit the growth of breast tumors. In this study, we synthesized LA-D-B1, a derivative of Abemaciclib, and investigated its anti-tumor effects in breast cancer. Methods: Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cloning and migration abilities were determined by colony formation assay and wound healing assay. Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay. The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting, which quantified the levels of proteins associated with the cyclin-dependent kinase (CDK) 4/6-cyclin D-Rb-E2F pathway. The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane (CAM) model. Results: The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation, induced apoptosis, and caused cell cycle arrest. Furthermore, LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway, including CDK4, CDK6 and E2F1. The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model. Conclusion: In this study, LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer. These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.

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