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Page 8 of 11 Peiró et al. J Cancer Metastasis Treat 2019;5:49 I http://dx.doi.org/10.20517/2394-4722.2018.109

Another compound that is known to modulate glycolysis in tumor cells is oroxylin A (OA), an active
flavonoid found in the plant Scutellaria baicalensis Georgi, widely used in Chinese medicine. In breast
cancer cells, OA was observed to decrease HIF-1α expression at the protein level. SIRT3 acts as a tumor
suppressor by regulating the mitochondrial protein manganese superoxide dismutase, reducing ROS levels.
In hypoxia, HIF-1α is stabilized by the inhibition of prolyl hydroxylases by ROS generation. The regulation
of O (Superoxide anion) by SIRT3 plays an important role in the activation of PHD induced by OA,
2-
destabilization of HIF-1α and suppression of glycolysis .
[52]
Ascofuranone is an antibiotic with antifungal properties that has been isolated from cultures of the
phytopathogenic fungus Ascochyta viciae. In addition to its antibiotic and antiviral effects, it also has some
physiological effects such as hypolipidemic activity, suppression of hypertension, immuno-modulation, and
amelioration of type II diabetes . Therefore, the effect of Ascofuranone on the expression of VEGF and
[53]
HIF-1α was examined, in ord er to determine if the antibiotic would also act on angiogenesis. Ascofuranone
decreased HIF-1α expression with a consequent decrease of VEGF expression in MDA-MB-231 cells in a
dose-dependent manner. Ascorfuranone was subsequently shown to inhibit the phosphorylation of Akt,
mTOR and p70S6K, inhibiting epidermal growth factor-induced protein synthesis . Another compound
[46]
that suppress HIF-1α by the Akt/mTOR/p70S6K and MAPK pathways in a dose-dependent manner is Ft1
(notoginsenoside Ft1) a saponin isolated from Panax notoginseng .
[54]

Andrographolide (Andro), a substance extracted from Andrographis paniculata, an Asian plant used for fever,
diarrhea and infectious diseases, also has anti-tumor characteristics such as attenuation of cell invasion,
inhibition of cell cycle progression, among others . Thus, the authors evaluated the relationship between
[55]
Andro and HIF-1α and its possible antitumor effect in breast cancer cells. In cultures of MDA-MB-231 and
T47D cells with Andro, a decrease in HIF-1α levels was observed in a dose-dependent manner . It was
[55]
also found that Andro down-regulated HIF-1α-mediated VEGF expression, which would be an indicator of
improvement in angiogenesis.

That some lactobacilli have a cytotoxic effect on neoplastic cells has already been described in the literature.
Based on that, Esfandiary et al. decided to use the culture supernatant of Lactobacillus crispatus (L. crispatus)
[56]
(LCS - L. crispatus supernatant) and Lactobacillus rhamnosus (L. rhamnosus) (LRS - L. rhamnosus supernatant)
in cultures of TNBC MDA-MB-231. It was found that LRS had a greater cytotoxic effect on MDA-MB-231 cells
than LCS. Treatment with LRS led to a decrease in mRNA levels of HIF-1α, HSP90 and SCL2A1 (GLUT1),
whereas LCS treatment down-regulated the expression of HSP90, SHARP1 (gene encoding proteins that act on
the degradation of HIF-1α) and VHL.

Diallyl trisulfides is an organic sulfur compound present in garlic that modulates various biological processes
and its effects were studied on the process of metastasis in breast cancer cells . According to the authors,
[57]
the compound at different concentrations inhibited not only the transcription but also the translation of
HIF-1α .
[57]
Berberine is an alkaloid purified from a plant of the genus Berberis, widely used in Eastern medicine,
and exhibits many pharmacological effects such as antihypertensive, antibacterial and antitumor effects.
Berberine was observed to inhibit the expression of P-glycoprotein (P-gp), which when up-expressed is a
marker of drug resistance. AMP-activated protein kinase (AMPK) is also seen in processes of resistance to
antitumor treatments, since it is a P-gp modulator in human cancer cells in hypoxia . Hypoxia was observed
[58]
to induce AMPK activation, elevating the protein levels of AMPK, P-gp and HIF-1α in MCF-7 cells. HIF-1α
was subsequently found to be a protein of the AMPK pathway and that regulates P-gp expression in MCF-7
cells, and that small doses of Berberine increased DOX chemosensitivity by inhibiting AMPK, subsequently
downregulating the expression of HIF-1α and of P-gp. Yet high doses of Berberine down-regulated HIF-1α,
which induced p53 activation, leading the mammary tumor cells to apoptosis in vitro .
[58]