Anti-Breast Cancer Activities of 8-Hydroxydaidzein by Targeting Breast Cancer Stem-Like Cells

Rajabi, Sadegh; Shojaee, Majid; Malmir, Ali; Tavirani, Mostafa Rezaei; Noori, Shokoofe

doi:10.18433/jpps30981

Cited by 11 publications

(6 citation statements)

References 38 publications

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“…The network map of MAPK and JAK/STAT-mediated apoptosis/anti-apoptosis is shown in Figure S2. It has been reported that 8-OHD triggered apoptosis in breast cancer stem-like cells (BCSCs) through blocking of the JAK/STAT signaling pathway [79]. Here, we found that JAK/STAT-related genes, SYK, STAT3, STAT5, and BIRC5, were all downregulated by 8-OHD in K562 cells, indicating that the JAK/STAT signaling pathway was attenuated.…”

Section: Analysis Of Signaling Pathways and Network Processes Using Kegg Biocarta And Metacorementioning

confidence: 62%

8-Hydroxydaidzein, an Isoflavone from Fermented Soybean, Induces Autophagy, Apoptosis, Differentiation, and Degradation of Oncoprotein BCR-ABL in K562 Cells

Yen

Wang

et al. 2020

Biomedicines

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8-Hydroxydaidzein (8-OHD, 7,8,4′-trihydoxyisoflavone) is a hydroxylated derivative of daidzein isolated from fermented soybean products. The aim of this study is to investigate the anti-proliferative effects and the underlying mechanisms of 8-OHD in K562 human chronic myeloid leukemia (CML) cells. We found that 8-OHD induced reactive oxygen species (ROS) overproduction and cell cycle arrest at the S phase by upregulating p21Cip1 and downregulating cyclin D2 (CCND2) and cyclin-dependent kinase 6 (CDK6) expression. 8-OHD also induced autophagy, caspase-7-dependent apoptosis, and the degradation of BCR-ABL oncoprotein. 8-OHD promoted Early Growth Response 1 (EGR1)-mediated megakaryocytic differentiation as an increased expression of marker genes, CD61 and CD42b, and the formation of multi-lobulated nuclei in enlarged K562 cells. A microarray-based transcriptome analysis revealed a total of 3174 differentially expressed genes (DEGs) after 8-OHD (100 μM) treatment for 48 h. Bioinformatics analysis of DEGs showed that hemopoiesis, cell cycle regulation, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) and Janus kinase/signal transducers and activators of transcription (JAK-STAT)-mediated apoptosis/anti-apoptosis networks were significantly regulated by 8-OHD. Western blot analysis confirmed that 8-OHD significantly induced the activation of MAPK and NF-κB signaling pathways, both of which may be responsible, at least in part, for the stimulation of apoptosis, autophagy, and differentiation in K562 cells. This is the first report on the anti-CML effects of 8-OHD and the combination of experimental and in silico analyses could provide a better understanding for the development of 8-OHD on CML therapy.

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Section: Analysis Of Signaling Pathways and Network Processes Using Kegg Biocarta And Metacorementioning

confidence: 62%

8-Hydroxydaidzein, an Isoflavone from Fermented Soybean, Induces Autophagy, Apoptosis, Differentiation, and Degradation of Oncoprotein BCR-ABL in K562 Cells

Yen

Wang

et al. 2020

Biomedicines

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“…Rajabi et al, 2020 also reported that 8-OHD triggered apoptosis in breast cancer stem-like cells through inhibiting the interleukin (IL)-6-mediated JAK2/STAT3 pathway [ 73 ]. STAT3 activation was found to be correlated with TKI resistance in CML [ 74 ].…”

Section: Resultsmentioning

confidence: 99%

8-Hydroxydaidzein Downregulates JAK/STAT, MMP, Oxidative Phosphorylation, and PI3K/AKT Pathways in K562 Cells

Wang

Chen

et al. 2021

Biomedicines

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A metabolite isolated from fermented soybean, 8-hydroxydaidzein (8-OHD, 7,8,4′-trihydroxyisoflavone, NSC-678112), is widely used in ethnopharmacological research due to its anti-proliferative and anti-inflammatory effects. We reported previously that 8-OHD provoked reactive oxygen species (ROS) overproduction, and induced autophagy, apoptosis, breakpoint cluster region-Abelson murine leukemia viral oncogene (BCR-ABL) degradation, and differentiation in K562 human chronic myeloid leukemia (CML) cells. However, how 8-OHD regulates metabolism, the extracellular matrix during invasion and metastasis, and survival signaling pathways in CML remains largely unexplored. High-throughput technologies have been widely used to discover the therapeutic targets and pathways of drugs. Bioinformatics analysis of 8-OHD-downregulated differentially expressed genes (DEGs) revealed that Janus kinase/signal transducer and activator of transcription (JAK/STAT), matrix metalloproteinases (MMPs), c-Myc, phosphoinositide 3-kinase (PI3K)/AKT, and oxidative phosphorylation (OXPHOS) metabolic pathways were significantly altered by 8-OHD treatment. Western blot analyses validated that 8-OHD significantly downregulated cytosolic JAK2 and the expression and phosphorylation of STAT3 dose- and time-dependently in K562 cells. Zymography and transwell assays also confirmed that K562-secreted MMP9 and invasion activities were dose-dependently inhibited by 8-OHD after 24 h of treatment. RT-qPCR analyses verified that 8-OHD repressed metastasis and OXPHOS-related genes. In combination with DisGeNET, it was found that 8-OHD’s downregulation of PI3K/AKT is crucial for controlling CML development. A STRING protein–protein interaction analysis further revealed that AKT and MYC are hub proteins for cancer progression. Western blotting revealed that AKT phosphorylation and nuclear MYC expression were significantly inhibited by 8-OHD. Collectively, this systematic investigation revealed that 8-OHD exerts anti-CML effects by downregulating JAK/STAT, PI3K/AKT, MMP, and OXPHOS pathways, and MYC expression. These results could shed new light on the development of 8-OHD for CML therapy.

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“…Previous studies have indicated that plant-derived phytochemicals have signi cant ant-cancer activities both alone or in combination with synthetic compounds [13,14]. Results of our previous investigation showed that 1-ferrocenyl-3-(4-methylsulfonylphenyl)propen-1-one (FMSP, Fig.…”

Section: Introductionmentioning

confidence: 99%

Naringenin Enhances Anti-Proliferation Effect of FMSP On K562 Human Chronic Myelogenous Leukemia Cells Via Targeting Calmodulin Signaling Pathway

Rajabi

Noori

Ashrafi

et al. 2021

Preprint

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Background: FMSP is a synthesized ferrocene derivative which possesses strong anti-proliferative and apoptosis inducing characteristics on tumor cells. Naringenin as a polyphenolic flavonoid is also able to reduce cell viability in tumors.Methods: Cell viability and proliferation of cancer cells after treatment with these agents were determined with MTT assay. To predict the possible interaction between calmodulin (CaM) and FMSP and naringenin, docking stuies were performed. By using fluorescence emission spectra, effects of FMSP and naringenin on CaM structure and activity were studied. CaM-dependent activation of phosphodiesterase 1 (PDE1) by FMSP in relation to naringenin and their combination were compared. Effects of these compounds on PDE1 inhibition, cAMP accumulation, and cAMP-dependent protein kinase A (PKA) activation were assayed. Results: Our results showed that combination of FMSP and naringenin had more inhibitory effects on CaM structure than FMSP and naringenin alone. Results of docking analyses also confirmed efficient intraction of the two compunds with hydrophobic pocket of calmodulin active site. Kinetic analyses of these agents interaction with CaM showed FMSP and naringenin both competitively inhibited PDE1 activation without changing Vmax parameter. FMSP and naringenin synergistically increased Km values in a higher level compared to FMSP or naringenin alone. Combination of these two agents also had more cytotoxic effects on K562 cells than FMSP alone. Conclusions: It was shown that mechanism of K562 cell proliferation inhibition by these compounds is based on CaM and consequent PDE inhibition followed by intracellular cAMP level elevation and increased PKA activity in a dose-dependent manner.

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Anti-Breast Cancer Activities of 8-Hydroxydaidzein by Targeting Breast Cancer Stem-Like Cells

Cited by 11 publications

References 38 publications

8-Hydroxydaidzein, an Isoflavone from Fermented Soybean, Induces Autophagy, Apoptosis, Differentiation, and Degradation of Oncoprotein BCR-ABL in K562 Cells

8-Hydroxydaidzein, an Isoflavone from Fermented Soybean, Induces Autophagy, Apoptosis, Differentiation, and Degradation of Oncoprotein BCR-ABL in K562 Cells

8-Hydroxydaidzein Downregulates JAK/STAT, MMP, Oxidative Phosphorylation, and PI3K/AKT Pathways in K562 Cells

Naringenin Enhances Anti-Proliferation Effect of FMSP On K562 Human Chronic Myelogenous Leukemia Cells Via Targeting Calmodulin Signaling Pathway

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