Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca 2+ concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.

Phytosterols, which are derived from plants, have various beneficial physiological effects, including anti-hypercholesterolemic, anti-inflammatory, and antifungal activities. The anticancer activities of natural products have attracted great attention, being associated with a low risk of side effects and not inducing antineoplastic resistance. β-sitosterol, a phytosterol, has been reported to have anticancer effects against fibrosarcoma and colon, breast, lung, and prostate cancer. However, there are no reports of its activity against ovarian cancer. Therefore, we investigated whether β-sitosterol shows anticancer effects against ovarian cancer using human ovarian cancer cell lines. We confirmed that β-sitosterol induced the apoptosis of ovarian cancer cells and suppressed their proliferation. It triggered pro-apoptosis signals and the loss of mitochondrial membrane potential, enhanced the generation of reactive oxygen species and calcium influx through the endoplasmic reticulum–mitochondria axis, and altered signaling pathways in human ovarian cancer cells. In addition, we observed inhibition of cell aggregation, suppression of cell growth, and decreased cell migration in ovarian cancer cells treated with β-sitosterol. Further, our data obtained using ovarian cancer cells showed that, in combination with standard anti-cancer drugs, β-sitosterol demonstrated synergistic anti-cancer effects. Thus, our study suggests that β-sitosterol may exert anti-cancer effects against ovarian cancer in humans.

IntroductionLeft ventricular hypertrophy and diastolic dysfunction in children and adolescents with essential hypertension tend to be underdiagnosed. The aims of this study were to investigate left ventricular hypertrophy and diastolic dysfunction in the subjects with essential hypertension defined by ambulatory blood pressure monitoring.MethodsA total of 38 Korean subjects aged 9–19 years without secondary causes of hypertension were reviewed. Ambulatory blood pressure monitoring was done in the 38 subjects to diagnose hypertension and gain the information of blood pressure pattern. The subjects were divided into two groups: a group with elevated blood pressure (BP) index (n = 29) and a group with normal BP index (n = 9). Two-dimensional ultrasound with M-mode imaging and tissue Doppler imaging were performed to measure left ventricular mass index and to assess the left ventricular diastolic dysfunction.ResultsLeft ventricular mass index(g/m2.7) was significantly higher in the group with elevated BP index than the group with normal BP index, but there were no differences in left ventricular diastolic dysfunction evaluated by E/A ratio and E/E’ ratio. Left ventricular mass index was related only with body mass index, while any of the ambulatory blood pressure monitoring parameters did not predict left ventricular hypertrophy. In terms of diastolic dysfunction in essential hypertension, E/E’ ratio in the subjects with left ventricular hypertrophy was higher than that in the other subjects without left ventricular hypertrophy.DiscussionLeft ventricular mass index is significantly correlated with body mass index in children and adolescents with essential hypertension, and the diastolic dysfunction could be in higher risk in subjects with left ventricular hypertrophy.

Osthole is a natural coumarin found in a variety of plants and has been reported to have diverse biological functions, including antimicrobial, antiviral, immunomodulatory, and anticancer effects. Here, we investigated the natural derivative osthole as a promising anticancer compound against ovarian cancer and evaluated its ability to suppress and abrogate tumor progression. In addition, we found the endoplasmic reticulum-mitochondrial axis-mediated anticancer mechanisms of osthole against ES2 and OV90 ovarian cancer cells and demonstrated its calcium-dependent pharmacological potential. Mechanistically, osthole was found to target the phosphatidylinositol 3-kinase/mitogen-activated protein kinase signaling pathway to facilitate tumor suppression in ovarian cancer. Furthermore, we identified the effects of osthole in a three-dimensional tumor-formation model using the zebrafish xenograft assay, providing convincing evidence of the pharmacological effects of osthole within the anchorage-independent tumor microenvironment. These findings suggest that osthole has strong potential as a pharmacological agent for targeting ovarian cancer.