164 research outputs found
In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.
Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has
been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog
(Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using
immunohistochemistry. We found a positive correlation between nuclear GLI1
expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining
significantly correlated with a lower tumor grade. Next, the in vitro effects of two
Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the
Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61.
GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer
cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing
the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation
of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21-
Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased
the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more
effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT-
61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse
breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of
TUBO cells in BALB/c mice to different extents. These findings suggest that targeting
the Hh pathway using antagonists that act downstream of SMO is a more efficient
strategy than using antagonists that act upstream of SMO for interrupting Hh signaling
in breast cancer
In vitro and in vivo antitumoral effects of combinations of polyphenols, or polyphenols and anticancer drugs: Perspectives on cancer treatment
Carcinogenesis is a multistep process triggered by genetic alterations that activate different signal transduction pathways and cause the progressive transformation of a normal cell into a cancer cell. Polyphenols, compounds ubiquitously expressed in plants, have anti-inflammatory, antimicrobial, antiviral, anticancer, and immunomodulatory properties, all of which are beneficial to human health. Due to their ability to modulate the activity of multiple targets involved in carcinogenesis through direct interaction or modulation of gene expression, polyphenols can be employed to inhibit the growth of cancer cells. However, the main problem related to the use of polyphenols as anticancer agents is their poor bioavailability, which might hinder the in vivo effects of the single compound. In fact, polyphenols have a poor absorption and biodistribution, but also a fast metabolism and excretion in the human body. The poor bioavailability of a polyphenol will affect the effective dose delivered to cancer cells. One way to counteract this drawback could be combination treatment with different polyphenols or with polyphenols and other anti-cancer drugs, which can lead to more effective antitumor effects than treatment using only one of the compounds. This report reviews current knowledge on the anticancer effects of combinations of polyphenols or polyphenols and anticancer drugs, with a focus on their ability to modulate multiple signaling transduction pathways involved in cancer
The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice
MiR-221 and miR-222 are two highly homologous microRNAs whose upregulation has been recently described in several types of human tumors, for some of which their oncogenic role was explained by the discovery of their target p27, a key cell cycle regulator. We previously showed this regulatory relationship in prostate carcinoma cell lines in vitro, underlying the role of miR-221/222 as inducers of proliferation and tumorigenicity
Lack of regulation of 11β-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism
Impact of Glycemic and Blood Pressure Variability on Surrogate Measures of Cardiovascular Outcomes in Type 2 Diabetic Patients
OBJECTIVE—The effect of glycemic variability (GV) on cardiovascular risk has not been fully
clarified in type 2 diabetes. We evaluated the effect of GV, blood pressure (BP), and oxidative
stress on intima-media thickness (IMT), left ventricular mass index (LVMI), flow-mediated dilation
(FMD), and sympathovagal balance (low frequency [LF]/high frequency [HF] ratio) in 26
type 2 diabetic patients (diabetes duration 4.41 6 4.81 years; HbA1c 6.70 6 1.25%) receiving
diet and/or metformin treatment, with no hypotensive treatment or complications.
RESEARCH DESIGN AND METHODS—Continuous glucose monitoring (CGM) data
were used to calculate mean amplitude of glycemic excursion (MAGE), continuous overall net
glycemic action (CONGA)-2, mean blood glucose (MBG), mean postprandial glucose excursion
(MPPGE), and incremental area under the curve (IAUC). Blood pressure (BP), circadian rhythm,
and urinary 15-F2t-isoprostane (8-iso-prostaglandin F2a [PGF2a]) were also evaluated. Subjects
were divided into dipper (D) and nondipper (ND) groups according to DBP.
RESULTS—IMT and LVMIwere increased inNDversusD(0.7760.08 vs. 0.6860.13 [P=0.04]
and 67 6 14 vs. 55 6 11 [P = 0.03], respectively). MBG, MAGE, and IAUC were significantly
associated with LF/HF ratio at night (r = 0.50, P = 0.01; r = 0.40, P = 0.04; r = 0.41, P = 0.04,
respectively), MPPGE was negatively associated with FMD (r =20.45, P = 0.02), andCONGA-2was positively associatedwith LVMI (r=0.55, P=0.006).TheDsystolic BP was negatively associated with IMT (r =20.43, P = 0.03) andwith LVMI (r =20.52, P = 0.01). Urinary 8-iso-PGF2a was positively associated with LVMI (r = 0.68 P , 0.001).
CONCLUSIONS—An impaired GV and BP variability is associated with endothelial and
cardiovascular damage in short-term diabetic patients with optimal metabolic control. Oxidative
stress is the only independent predictor of increased LV mass and correlates with glucose and BP variability
Psychoneuroendocrine adaptation to the stress of performance: multiple aspects and one answer
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