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Cited by 82Flavonoids in Medical ResearchCancer, Hypoxia, and MetabolismEstrogen and related hormone effects

Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

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Chen, Yan, Zhang, Jingyu, Zhang, Minqin, Song, Yuxuan, Zhang, Yue, Fan, Shuangqin, Ren, Shuang, Fu, Lingyun +3 more·2021·Clinical and Translational Medicine
DOI 10.1002/ctm2.577PMC PMC8567056
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Abstract

Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM‐resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM‐resistant cells. It also enhanced the TAM‐induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan–Meier plotter database showed that HIF‐1α expression was inversely correlated with TAM therapeutic response in NCI‐60 cancer cells and breast cancer patients. HIF‐1α expression was increased in TAM‐resistant cells due to an increase in mRNA levels and reduced ubiquitin‐mediated degradation. Baicalein reduced HIF‐1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase‐mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia‐response element, and transcriptional activity of HIF‐1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF‐1α‐targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF‐1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM‐induced mitochondrial apoptotic pathway. The HIF‐1α stabilizer dimethyloxallyl glycine prevented the baicalein‐induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM‐induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF‐1α–mediated aerobic glycolysis and mitochondrial dysfunction.

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  • Baicalein reverses hypoxia-induced resistance to tamoxifen through downregulation of HIF-1α levels in breast cancer cells.

    “BE has been shown to reverse hypoxia-induced resistance to tamoxifen (TAM) through the downregulation of HIF-1α levels in breast cancer cells.209”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [209]

    The Discussion reports that baicalein reduces HIF-1α expression and resensitizes tamoxifen-resistant breast cancer cells. But the Introduction says HIF-1α is activated in these resistant cells even under normoxic conditions; the cited study does not establish that the resistance baicalein reversed was hypoxia-induced. The indexed passages provide no page numbers. (LLM, conf=0.88)

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  1. [1]Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71: 209‐ 249. 33538338
  2. [2]Dobovisek L, Krstanovic F, Borstnar S, Debeljak N. Cannabinoids and hormone receptor‐positive breast cancer treatment. Cancers (Basel). 2020; 12(3): 525. PMC7139952 32106399
  3. [3]Bense RD, Qiu SQ, de Vries EGE, Schroder CP, Fehrmann RSN. Considering the biology of late recurrences in selecting patients for extended endocrine therapy in breast cancer. Cancer Treat Rev. 2018; 70: 118‐ 126. 30149225
  4. [4]Mills JN, Rutkovsky AC, Giordano A. Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors. Curr Opin Pharmacol. 2018; 41: 59‐ 65. 29719270 PMC6454890
  5. [5]Mishra A, Srivastava A, Pateriya A, Tomar MS, Mishra AK, Shrivastava A. Metabolic reprograming confers tamoxifen resistance in breast cancer. Chem‐Biol Interact. 2021; 347: 109602. 10.1016/j.cbi.2021.109602 34331906 · DOI
  6. [6]Leignadier J, Dalenc F, Poirot M, Silvente‐Poirot S. Improving the efficacy of hormone therapy in breast cancer: the role of cholesterol metabolism in SERM‐mediated autophagy, cell differentiation and death. Biochem Pharmacol. 2017; 144: 18‐ 28. 28642035
  7. [7]McAleese CE, Choudhury C, Butcher NJ, Minchin RF. Hypoxia‐mediated drug resistance in breast cancers. Cancer Lett. 2021; 502: 189‐ 199. 33278499
  8. [8]Jia X, Hong Q, Lei L, et al. Basal and therapy‐driven hypoxia‐inducible factor‐1alpha confers resistance to endocrine therapy in estrogen receptor‐positive breast cancer. Oncotarget. 2015; 6(11): 8648‐ 8662. 25929338 PMC4496173
  9. [9]Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF‐alpha to the von Hippel‐Lindau ubiquitylation complex by O2‐regulated prolyl hydroxylation. Science. 2001; 292(5516): 468‐ 472. 11292861
  10. [10]Akanji MA, Rotimi D, Adeyemi OS. Hypoxia‐inducible factors as an alternative source of treatment strategy for cancer. Oxid Med Cell Longev. 2019; 2019: 8547846. 31485300 PMC6710762
  11. [11]Woo YM, Shin Y, Lee EJ, et al. Inhibition of aerobic glycolysis represses Akt/mTOR/HIF‐1alpha axis and restores tamoxifen sensitivity in antiestrogen‐resistant breast cancer cells. PLoS One. 2015; 10(7): e0132285. 26158266 PMC4497721
  12. [12]Nazarewicz RR, Zenebe WJ, Parihar A, et al. Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase. Cancer Res. 2007; 67(3): 1282‐ 1290. 17283165
  13. [13]Razandi M, Pedram A, Jordan VC, Fuqua S, Levin ER. Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer. Oncogene. 2013; 32(27): 3274‐ 3285. 22907432 PMC3505272
  14. [14]Tuquet C, Dupont J, Mesneau A, Roussaux J. Effects of tamoxifen on the electron transport chain of isolated rat liver mitochondria. Cell Biol Toxicol. 2000; 16(4): 207‐ 219. 11101003
  15. [15]Larosche I, Letteron P, Fromenty B, et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther. 2007; 321(2): 526‐ 535. 17277197
  16. [16]Naito A, Carcel‐Trullols J, Xie CH, Evans TT, Mizumachi T, Higuchi M. Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line. Int J Cancer. 2008; 122(7): 1506‐ 1511. 17990320 PMC2293290
  17. [17]He M, Jin Q, Chen C, et al. The miR‐186‐3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in breast cancer cells. Oncogene. 2019; 38(28): 5551‐ 5565. 30967627
  18. [18]Zhang X, Zhao H, Li Y, et al. The role of YAP/TAZ activity in cancer metabolic reprogramming. Mol Cancer. 2018; 17(1): 134. 30176928 PMC6122186
  19. [19]Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF‐1 and PI3K. Mol Biol Rep. 2015; 42(4): 841‐ 851. 25689954
  20. [20]Zhang H, Gao P, Fukuda R, et al. HIF‐1 inhibits mitochondrial biogenesis and cellular respiration in VHL‐deficient renal cell carcinoma by repression of C‐MYC activity. Cancer Cell. 2007; 11(5): 407‐ 420. 17482131
  21. [21]Zhang H, Bosch‐Marce M, Shimoda LA, et al. Mitochondrial autophagy is an HIF‐1‐dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008; 283(16): 10892‐ 10903. 18281291 PMC2447655
  22. [22]Po LS, Chen ZY, Tsang DS, Leung LK. Baicalein and genistein display differential actions on estrogen receptor (ER) transactivation and apoptosis in MCF‐7 cells. Cancer Lett. 2002; 187(1‐2): 33‐ 40. 12359348
  23. [23]Shang D, Li Z, Zhu Z, et al. Baicalein suppresses 17‐beta‐estradiol‐induced migration, adhesion and invasion of breast cancer cells via the G protein‐coupled receptor 30 signaling pathway. Oncol Rep. 2015; 33(4): 2077‐ 2085. 25672442
  24. [24]Chen Y, Wang J, Hong DY, et al. Baicalein has protective effects on the 17beta‐estradiol‐induced transformation of breast epithelial cells. Oncotarget. 2017; 8(6): 10470‐ 10484. 28060756 PMC5354673
  25. [25]Chen Y, Hong DY, Wang J, et al. Baicalein, unlike 4‐hydroxytamoxifen but similar to G15, suppresses 17beta‐estradiol‐induced cell invasion, and matrix metalloproteinase‐9 expression and activation in MCF‐7 human breast cancer cells. Oncol Lett. 2017; 14(2): 1823‐ 1830. 28789417 PMC5529993
  26. [26]Koh SY, Moon JY, Unno T, Cho SK. Baicalein suppresses stem cell‐like characteristics in radio‐ and chemoresistant MDA‐MB‐231 human breast cancer cells through up‐regulation of IFIT2. Nutrients. 2019; 11(3): 624. PMC6471144 30875792
  27. [27]Meng L, Xia X, Yang Y, et al. Co‐encapsulation of paclitaxel and baicalein in nanoemulsions to overcome multidrug resistance via oxidative stress augmentation and P‐glycoprotein inhibition. Int J Pharm. 2016; 513(1‐2): 8‐ 16. 27596118
  28. [28]Chen F, Zhuang M, Zhong C, et al. Baicalein reverses hypoxia‐induced 5‐FU resistance in gastric cancer AGS cells through suppression of glycolysis and the PTEN/Akt/HIF‐1alpha signaling pathway. Oncol Rep. 2015; 33(1): 457‐ 463. 25333894
  29. [29]Huang L, Peng B, Nayak Y, et al. Baicalein and baicalin promote melanoma apoptosis and senescence via metabolic inhibition. Front Cell Dev Biol. 2020; 8: 836. 32984331 PMC7477299
  30. [30]Chen Y, Chen ZY, Chen L, et al. Shikonin inhibits triple‐negative breast cancer‐cell metastasis by reversing the epithelial‐to‐mesenchymal transition via glycogen synthase kinase 3beta‐regulated suppression of beta‐catenin signaling. Biochem Pharmacol. 2019; 166: 33‐ 45. 31071331
  31. [31]Győrffy B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Comput Struct Biotechnol J. 2021; 19: 4101‐ 4109. 34527184 PMC8339292
  32. [32]Yang J, AlTahan A, Jones DT, et al. Estrogen receptor‐alpha directly regulates the hypoxia‐inducible factor 1 pathway associated with antiestrogen response in breast cancer. Proc Natl Acad Sci U S A. 2015; 112(49): 15172‐ 15177. 26598706 PMC4679044
  33. [33]Shmueli MD, Levy‐Kanfo L, Haj E, Schoenfeld AR, Gazit E, Segal D. Arginine refolds, stabilizes, and restores function of mutant pVHL proteins in animal model of the VHL cancer syndrome. Oncogene. 2019; 38(7): 1038‐ 1049. 30194449
  34. [34]Zheng A, Kallio A, Harkonen P. Tamoxifen‐induced rapid death of MCF‐7 breast cancer cells is mediated via extracellularly signal‐regulated kinase signaling and can be abrogated by estrogen. Endocrinology. 2007; 148(6): 2764‐ 2777. 17363451
  35. [35]Nagao A, Kobayashi M, Koyasu S, Chow CCT, Harada H. HIF‐1‐dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int J Mol Sci. 2019; 20(2): 238. PMC6359724 30634433
  36. [36]Guerra F, Arbini AA, Moro L. Mitochondria chemoresistance cancer. Biochim Biophys Acta Bioenerg. 2017; 1858(8): 686‐ 699. 28161329
  37. [37]Sansone P, Savini C, Kurelac I, et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy‐resistant breast cancer. Proc Natl Acad Sci U S A. 2017; 114(43): E9066‐ E9075. 29073103 PMC5664494
  38. [39]Guo L, Cui C, Wang J, et al. PINCH‐1 regulates mitochondrial dynamics to promote proline synthesis and tumor growth. Nat Commun. 2020; 11(1): 4913. 33004813 PMC7529891
  39. [40]Loson OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell. 2013; 24(5): 659‐ 667. 23283981 PMC3583668
  40. [41]Shi J, Yu T, Song K, et al. Dexmedetomidine ameliorates endotoxin‐induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF‐1a/HO‐1 signaling pathway. Redox Biol. 2021; 41: 101954. 33774474 PMC8027777
  41. [42]Saha P, Mandal T, Talukdar AD, et al. DNA polymerase eta: a potential pharmacological target for cancer therapy. J Cell Physiol. 2021; 236(6): 4106‐ 4120. 33184862
  42. [43]Shnaider PV, Ivanova OM, Malyants IK, et al. New insights into therapy‐induced progression of cancer. Int J Mol Sci. 2020; 21(21): 7872. PMC7660620 33114182
  43. [44]Damen MPF, van Rheenen J, Scheele C. Targeting dormant tumor cells to prevent cancer recurrence. FEBS J. 2020. 10.1111/febs.15626. 33190412 · DOI
  44. [45]Ma L, Zong X. Metabolic symbiosis in chemoresistance: refocusing the role of aerobic glycolysis. Front Oncol. 2020; 10: 5. 32038983 PMC6992567
  45. [46]Dong Q, Zhou C, Ren H, et al. Lactate‐induced MRP1 expression contributes to metabolism‐based etoposide resistance in non‐small cell lung cancer cells. Cell Commun Signal. 2020; 18(1): 167. 33097055 PMC7583203
  46. [47]Brown TP, Bhattacharjee P, Ramachandran S, et al. The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen‐presenting cells in the tumor microenvironment. Oncogene. 2020; 39(16): 3292‐ 3304. 32071396
  47. [48]Liu X, Miao W, Huang M, Li L, Dai X, Wang Y. Elevated hexokinase II expression confers acquired resistance to 4‐hydroxytamoxifen in breast cancer cells. Mol Cell Proteomics. 2019; 18(11): 2273‐ 2284. 31519767 PMC6823848
  48. [49]Tu SH, Chang CC, Chen CS, et al. Increased expression of enolase alpha in human breast cancer confers tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat. 2010; 121(3): 539‐ 553. 19655245
  49. [50]Woo SH, Seo SK, Park Y, et al. Dichloroacetate potentiates tamoxifen‐induced cell death in breast cancer cells via downregulation of the epidermal growth factor receptor. Oncotarget. 2016; 7(37): 59809‐ 59819. 27494858 PMC5312350
  50. [51]Stothers CL, Luan L, Fensterheim BA, Bohannon JK. Hypoxia‐inducible factor‐1alpha regulation of myeloid cells. J Mol Med (Berl). 2018; 96(12): 1293‐ 1306. 30386909 PMC6292431
  51. [52]Elswood J, Pearson SJ, Payne HR, Barhoumi R, Rijnkels M, WP W. Autophagy regulates functional differentiation of mammary epithelial cells. Autophagy. 2020: 1‐ 19. PMC8007166 31983267
  52. [53]Yu M, Zhou Y, Shi Y, et al. Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life. 2007; 59(7): 450‐ 457. 17654121
  53. [55]Yuan P, Yang T, Mu J, et al. Circadian clock gene NPAS2 promotes reprogramming of glucose metabolism in hepatocellular carcinoma cells. Cancer Lett. 2020; 469: 498‐ 509. 31765736
  54. [56]Labuschagne CF, Cheung EC, Blagih J, Domart MC, Vousden KH. Cell clustering promotes a metabolic switch that supports metastatic colonization. Cell Metab. 2019; 30(4): 720‐ 734 e725. 31447323 PMC6863392
  55. [57]Reznik E, Miller ML, Senbabaoglu Y, et al. Mitochondrial DNA copy number variation across human cancers. Elife. 2016; 5: e10769. 26901439 PMC4775221
  56. [58]Milliken AS, Kulkarni CA, Brookes PS. Acid enhancement of ROS generation by complex‐I reverse electron transport is balanced by acid inhibition of complex‐II: relevance for tissue reperfusion injury. Redox Biol. 2020; 37: 101733. 33007502 PMC7527751
  57. [59]Martinou JC, Youle RJ. Mitochondria in apoptosis: Bcl‐2 family members and mitochondrial dynamics. Dev Cell. 2011; 21(1): 92‐ 101. 21763611 PMC3156409
  58. [61]Li C, Kim M, Choi H, Choi J. Effects of baicalein on the pharmacokinetics of tamoxifen and its main metabolite, 4‐hydroxytamoxifen, in rats: possible role of cytochrome P450 3A4 and P‐glycoprotein inhibition by baicalein. Arch Pharm Res. 2011; 34(11): 1965‐ 1972. 22139696

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  • Drug repurposing for cancer therapy

    Xia, Y., Sun, M., Huang, H., & Jin, W.-L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01808-1 · Cited by 443 · see citing works

    “209 From a molecular perspective, the 6-phosphogluconate dehydrogenase-driven oxidative pentose phosphate pathway is thought to facilitate the reshaping of histone H3K9 and DNA methylation patterns during tumor progression.”
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Authors
Chen, Y., Zhang, J., Zhang, M., Song, Y., Zhang, Y., Fan, S., Ren, S., Fu, L., Zhang, N., Hui, H., & Shen, X.
Affiliations
  • Guiyang Medical University (CN)
  • China Pharmaceutical University (CN)
Corresponding author
  • Hui, Hui
  • Shen, Xiangchun
ORCID
Venue
Clinical and Translational Medicine
Publisher
Wiley
Published
2021-11
Volume
11
Issue
11
Pages
e577-e577
ISSN
2001-1326 (ISSN-L)
DOI
10.1002/ctm2.577
PMC
PMC8567056
OpenAlex
W3214733033
Cited by
82
References
3
Citations by year
2026: 12 · 2025: 18 · 2024: 19 · 2023: 18 · 2022: 14 · 2021: 1
FWCI
7.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical and Translational Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81860648, 81873046 : U1812403‐4‐4)
  • Natural Science Foundation of Guizhou Province (QKHJC‐ZK (2021)‐YB527)
Topics
  • Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
baicalein, tamoxifen resistance, breast cancer, HIF-1α, aerobic glycolysis, mitochondrial dysfunction, PHD2, von Hippel-Lindau protein, ubiquitin-mediated proteolysis, mitochondrial apoptosis, reactive oxygen species, drug sensitization
MeSH terms
Warburg Effect, Oncologic, Animals, Breast Neoplasms, Disease Models, Animal, Drug Resistance, Female, Tamoxifen, Mice, Inbred NOD, Mitochondrial Diseases, Flavanones, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Real-Time Polymerase Chain Reaction

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