The high recurrence rates of colorectal cancer have been associated with a small population of cancer stem cells (CSCs) that are resistant to the standard chemotherapeutic drug, 5-fluorouracil (5FU). Thymoquinone (TQ) has shown promising antitumor properties on numerous cancer systems both
in vitro
and
in vivo
; however, its effect on colorectal CSCs is poorly established. Here, we investigated TQ’s potential to target CSCs in a three-dimensional (3D) sphere-formation assay enriched for a population of colorectal cancer stem/progenitor cells. Our results showed a significant decrease in self-renewal potential of CSC populations enriched from 5FU-sensitive and resistant HCT116 cells at 10-fold lower concentrations when compared to 2D monolayers. TQ decreased the expression levels of colorectal stem cell markers CD44 and Epithelial Cell Adhesion Molecule EpCAM and proliferation marker Ki67 in colonospheres derived from both cell lines and reduced cellular migration and invasion. Further investigation revealed that TQ treatment led to increased TUNEL positivity and a dramatic increase in the amount of the DNA damage marker gamma H2AX particularly in 5FU-resistant colonospheres, suggesting that the diminished sphere forming ability in TQ-treated colonospheres is due to induction of DNA damage and apoptotic cell death. The intraperitoneal injection of TQ in mice inhibited tumor growth of spheres derived from 5FU-sensitive and 5FU-resistant HCT116 cells. Furthermore, TQ induced apoptosis and inhibited NF-κB and MEK signaling in mouse tumors. Altogether, our findings document TQ’s effect on colorectal cancer stem-like cells and provide insights into its underlying mechanism of action.
Objective: To determine the association of cardiometabolic comorbidities
and use of cardiometabolic medications with diagnosis of uterine
leiomyoma (UL). Design: Cross-sectional study. Setting: The John Hopkins
Health System. Population or sample: Women 18 years or older who had at
least one visit or hospital encounter and one blood pressure
measurement. Methods: Aggregate-level data from January 1, 2013 to
January 1, 2020 were collected using SlicerDicer feature of Epic
electronic medical record system. Participants were assigned as cases or
controls according to UL status. The individual prevalence of each
pre-specified cardiometabolic comorbidity and relevant prescription
medications was obtained. Main Outcome Measures: We used prevalence odds
ratios to assess the association of cardiometabolic comorbidities and
use of medications with UL. Results: The study included 27,703 women
with UL. Women with UL were more likely to be obese (2.56; 95%CI,
2.49-2.63), have metabolic syndrome (1.82; 95%CI, 1.51-2.19), essential
hypertension (1.45; 95%CI, 1.42-1.49), diabetes mellitus (1.29; 95%CI,
1.24-1.33) and hyperlipidemia (1.23; 95%CI, 1.19-1.26). These
associations were stronger among younger women and persisted after
excluding those who had a hysterectomy. Notably, statins were the only
medications associated with a lower UL risk (0.81; 95%CI, 0.79-0.84).
Conclusions: UL is associated with an unfavorable cardiometabolic
profile in women. If found to be more definitively correlated,
prevention and early management of cardiometabolic risk factors may
decrease the incidence of UL, and screening women UL for cardiometabolic
comorbidities may aid in cardiovascular disease prevention. Funding: NIH
grant [1R01HD094380-01] to Mostafa A. Borahay. Keywords:
Cardiometabolic comorbidity; Statins; Uterine Fibroids
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