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LA-CB1, a novel Abemaciclib derivative induces apoptosis in breast cancer cells by inhibiting the CDK4/6-Cyclin D-Rb-E2F pathway path

ABSTRACT: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) characterized by deletion of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her-2). It accounts for 10.0% to 20.8% of all pathological types of BC, has specific biological behavior and clinicopathological features, and has a worse prognosis than other types. TNBC usually has a high mortality and recurrence rate, and a poor prognosis after surgery, radiation, chemotherapy, and endocrine therapy. There are no conventional and effective treatments to control its progression. Therefore, we designed and developed a derivative based on Abemaciclib, named LA-CB1. To investigate the influence of LA-CB1 on biological function of TNBC. We use the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT) to detect the viability of breast cancer cells. Evaluation of drug effects on cell migration and invasion by Transwell assays. Cell clone formation assay detects cell proliferation ability after drug addition. Subsequently, we determined the clinical significance and functional role of LA-CB1 through chick embryo experiments. Then, transcriptome sequencing technology (RNA-Seq) and bioinformatics methods were used to study the main pathway of LA-CB1 action on MDA-MB-231 cells. Western Blot assay verified the effect of LA-CB1 on the expression of CDK4/6-CyclinD1-Rb-E2F pathway protein. The compound LA-CB1 can inhibit the proliferation, colony formation, migration and invasion of TNBC cells. Effect of compound LA-CB1 on apoptosis and cell cycle detected by flow cytometry. The expression levels of CDK4, CDK6, CyclinD1, E2F1 and p-Rb proteins were positively correlated with LA-CB1 concentration. In summary, LA-CB1 showed a good anti-tumor cell proliferation effect, showing potential anti-TNBC drug candidate properties. This study provides new ideas and possibilities for TNBC treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276256 | GEO | 2024/10/11

REPOSITORIES: GEO

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Project description:PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and arrayCGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort ovarian cancer patients. Concentration-dependent anti-proliferative effects of PD-0332991were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, Rb, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration and time dependent manner, and enhanced the effects of chemotherapy. Rb proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and associated with adverse clinical outcome (progression free survival, adjusted relative risk 1.49, 95%CI 0.99-2.22, p =0.054). PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. Gene expression of 40 individual ovarian cell lines relative to an ovarian cell line reference mix containing equal amounts of 41 ovarian cell lines (including OCC-1 which was later identified as originating from mouse). The expression data was correllated with cell line growth response to CDK 4/6 inhibitor PD-0332991 to identify genes associated with drug sensitivity and resistance.

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LA-CB1, a novel Abemaciclib derivative induces apoptosis in breast cancer cells by inhibiting the CDK4/6-Cyclin D-Rb-E2F pathway path

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