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Page 6 of 11 Peiró et al. J Cancer Metastasis Treat 2019;5:49 I http://dx.doi.org/10.20517/2394-4722.2018.109
signaling is known to be a regulator of HIF-1α expression, and on that account the specific inhibitor
LY290004, which inhibited Akt phosphorylation and consequently prevented Brachyury-induced HIF-1α
expression, revealing that Brachyury is a transcription factor that can be targeted in breast cancer treatments
along with HIF-1α .
[39]
A HIF-1α putative inhibitor is T2A or TSN [36,40-42] . Breast cancer cells treated with this drug showed a
decrease in expression levels of HIF-1a and VEGF proportional to the concentration of T2A administered .
[36]
T2A was also used to inhibit EMT in breast cancer cells via HIF-1α . Two cell lines with hypoxia-induced
[40]
doxorubicin (DOX) resistance in relation to T2A, MCF-1 and HCC1937, were analyzed. T2A decreased the
DOX resistance of both lines in hypoxia partially via HIF-1α [40,41] . It was also found that T2A reduced the
viability and proliferation rate in both cell lines, indicating that T2A can target the cell cycle .
[40]
Dutasteride, a double-blocker of type 1 and type 2 isoforms of the steroid-5α-reductase (SRD541) gene is
used in the treatment of benign prostatic hyperplasia. As SRD541 is highly expressed in breast tumor cells,
Dutasteride was tested in MDA-MB-231 and MDA-MB-468 cells in vitro . MDA-MB-231 cells showed a
[43]
decrease in VEGF expression, while the detection of HIF-1α was at the limit of detection of the technique
employed. MDA-MB-468 cells had decreased VEGF and HIF-1α, showing the potential effect of Dutasteride
treatment in response to chemotherapy of TNBCs via altered protein expression of HIF-1α and VEGF.
In order to verify the effects of pigallocatechin-3-gallate on the expression of HIF-1α and VEGF in breast
cancer cells, MCF-7 cells were treated with different concentrations of this compound . These cells had a
[44]
dramatic decrease in growth and decreased expression of VEGF and HIF-1α in a dose-dependent manner.
Also working with cells, Dewangan et al. evaluated the inhibitory effects of centchroman, a non-steroidal
[23]
oral contraceptive on HIF-1α. As was expected, an elevated expression of HIF-1α in cells prior to treatment
was observed, which was inhibited with drug administration. After treatment, a decrease in VEGF/VEGFR2
expression was observed, with a consequent decrease in angiogenesis . Sarkar et al. , on the other hand,
[10]
[23]
demonstrated that the administration of phenethyl isothiocyanate, an organic sulfur of the Isotiosianate
family found in cruciferous plants decreased HIF-1α expression in normoxia and hypoxia. In addition,
administration of N-acetyl cysteine, a known antioxidant, which had been used as a positive control was also
observed to inhibit HIF-1α expression. A correlation analysis was then performed to try to determine the
association between the parameters involved in the low regulation of HIF-1α by phenethyl isothiocyanate. A
positive correlation was found between HIF-1α and HSP90, and these two parameters were correlated with
reactive oxygen species (ROS). According to the authors, ROS can be considered the main regulator of both
HIF-1α and HSP90 .
[10]
The drug M410 [(Z)-3,4',5-trimethoxylstilbene-3'-Ophosphate disodium, a CA4 analog], which is a potent
tubulin polymerization inhibitor in bovine brain in vitro, had its inhibitory potential for HIF-1α evaluated
[45]
by Yang et al. Upon treatment, the expression of HIF-1β was found to be unaltered; however, HIF-1α
expression was decreased. The amount of VEGF and glucose transporter 1 messenger RNA in the cells was
also analyzed, which was very low in relative to normality, showing that M410 was directly involved in the
transcriptional activity of HIF-1α .
[45]
DCQ (2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide) contains an N-oxyde portion (present in
hypoxia-activated drugs used in cancer treatments) similar to tirapazamine (TPZ) used in treatments against
other types of cancer, but inefficient in breast cancer . Similarly to the results with TPZ treatments found
[46]
in the literature, DCQ induced an increase in p-Akt levels and a reduction in p-mTOR levels suggesting
possible anti-translational activity in MCF-7 cells, which would decrease the rates of HIF-1α. DCQ was
identified as a promising drug in the treatment of breast cancer because it exhibits pro-apoptotic and anti-
metastatic features by reducing HIF-1α and the post-HIF-1α gene signaling cascade .
[46]