BC-N102 suppress breast cancer tumorigenesis by interfering with cell cycle regulatory proteins and hormonal signaling, and induction of time-course arrest of cell cycle at G1/G0 phase

Abstract

Mechanisms of breast cancer progression and invasion, often involve alteration of hormonal signaling, and upregulation and/or activation of signal transduction pathways that input to cell cycle regulation . Herein, we describe a rationally designed first-in-class novel small molecule inhibitor for targeting oncogenic and hormonal signaling in ER-positive breast cancer. BC-N102 treatment exhibits dose-dependent cytotoxic effects against ER+ breast cancer cell lines. BC-N102 exhibited time course- and dose-dependent cell cycle arrest via downregulation of the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-Akt, CDK2, and CDK4 while increasing p38 mitogen-activated protein kinase (MAPK), and mineralocorticoid receptor (MR) signaling in breast cancer cell line. In addition, we found that BC-N102 suppressed breast cancer tumorigenesis in vivo and prolonged the survival of animals. Our results suggest that the proper application of BC-N102 may be a beneficial chemotherapeutic strategy for ER+ breast cancer patients.

Identification of a novel immune-inflammatory signature of COVID-19 infections, and evaluation of pharmacokinetics and therapeutic potential of RXn-02, a novel small-molecule derivative of quinolone

“…In vitro antiproliferative activities of RXn-02 against hub gene-expressing cell lines, including K-562, MCF-7, and A549 cells, and four other human cell lines of lung origin, viz., HOP-62, NCI–H226, NCI–H322 M, and NCI–H522 cells, were evaluated using the sulforhodamine B (SRB) reagent protocol [ 33 ]. About 5000–40,000 viable cells were seeded in each well of 96-well plates for 24 h. After 24 h of incubation, the medium was replaced, and cells were treated with RXn-02 at increasing concentrations of 0, 0.1, 1.0, 10, and 100 μM for 48 h. After incubation, cells were washed with 1% phosphate-buffered saline (PBS) and incubated with 10% trichloroacetic acid (TCA) at room temperature for 1 h [ 34 ]. The plates were washed with double-distilled (dd)H 2 O, and further incubated with 0.4% SRB for 60 min.…”

Prognostic and Genomic Analysis of Proteasome 20S Subunit Alpha (PSMA) Family Members in Breast Cancer

“…While existing evidence-based treatment strategies use the classical hormonal factors, including the progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor (HER)-2, to stratify BRCA prior to determining the most suitable treatment for patients, plenty of immunohistochemical markers, such as Ki-67, p53, and E-cadherin, are simultaneously employed as predictive tools for those subtypes that still lack druggable molecular targets [ 6 , 7 , 8 , 9 , 10 ]. Over the past few years, studies of the genetic alterations and dysfunction of signal transduction pathways that highly contribute to the advent of numerous predictive biomarkers, including transcriptomic data and messenger (m)RNA levels, have opened up the possibility of having effective therapeutics and have been useful in predicting tumor grades, drug responsiveness, and risks of recurrence of intrinsic subtypes [ 11 , 12 , 13 ].…”

Glutamine synthetase regulates the immune microenvironment and cancer development through the inflammatory pathway

“…In response to this situation, existing salvage therapies for tamoxifen-resistant (TR) patients have been well-designed, including fulvestrant, cyclindependent kinase 4/6 (CDK4/6) inhibitors, and histone deacetylase (HDAC) inhibitors [19][20][21]. However, not all patients respond properly to these therapies [22][23][24][25].…”