1,126
Views
0
CrossRef citations to date
0
Altmetric
Review

Molecular pharmacology of the onco-TRP channel TRPV6

ORCID Icon & ORCID Icon
Article: 2266669 | Received 31 Jul 2023, Accepted 29 Sep 2023, Published online: 15 Oct 2023

References

  • Neuberger A, Nadezhdin KD, Sobolevsky AI. Methods Enzymol. Vol. 652, 31–20. Elsevier; 2021
  • Hoenderop JG, Vennekens R, Muller D, et al. Function and expression of the epithelial Ca2+ channel family: comparison of mammalian ECaC1 and 2. J Physiol. 2001;537(3):747–761. doi: 10.1113/jphysiol.2001.012917
  • Vennekens R, Voets T, Bindels RJ, et al. Current understanding of mammalian TRP homologues. Cell Calcium. 2002;31(6):253–264. pii. doi: 10.0143/4160(02)00055-6.
  • den Dekker E, Hoenderop JG, Nilius B, et al. The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. Cell Calcium. 2003;33:497–507. pii. doi: 10.0143/416003000654
  • Fecher-Trost C, Weissgerber P, Wissenbach U. TRPV6 channels. Mammalian Transient Receptor Potential (TRP) Cation Channels. 2014;359–384.
  • Zakharian E, Cao C, Rohacs T. Intracellular ATP supports TRPV6 activity via lipid kinases and the generation of PtdIns(4,5) P2. FASEB J. 2011;25:3915–3928. doi: 10.1096/fj.11-184630
  • Cai R, Liu X, Zhang R, et al. Autoinhibition of TRPV6 channel and regulation by PIP2. iScience. 2020;23(9):101444. doi: 10.1016/j.isci.2020.101444
  • Thyagarajan B, Lukacs V, Rohacs T. Hydrolysis of phosphatidylinositol 4,5-bisphosphate mediates calcium-induced inactivation of TRPV6 channels. J Biol Chem. 2008;283(22):14980–14987. doi: 10.1074/jbc.M704224200
  • Voets T, Janssens A, Prenen J, et al. Mg2+-dependent gating and strong inward rectification of the cation channel TRPV6. J Gen Physiol. 2003;121:245–260. doi: 10.1085/jgp.20028752
  • Owsianik G, Talavera K, Voets T, et al. Permeation and selectivity of TRP channels. Annu Rev Physiol. 2006;68(1):685–717. doi: 10.1146/annurev.physiol.68.040204.101406
  • Lambers TT, Weidema AF, Nilius B, et al. Regulation of the mouse epithelial Ca2+ channel TRPV6 by the Ca2+-sensor calmodulin. J Biol Chem. 2004;279(28):28855–28861. doi: 10.1074/jbc.M313637200
  • Derler I, Hofbauer M, Kahr H, et al. Dynamic but not constitutive association of calmodulin with rat TRPV6 channels enables fine tuning of Ca2+-dependent inactivation. J Physiol. 2006;577:31–44. doi: 10.1113/jphysiol.2006.118661
  • Nilius B, Prenen J, Hoenderop JG et al. Fast and slow inactivation kinetics of the Ca2+ channels ECaC1 and ECaC2 (TRPV5 and TRPV6). Role of the intracellular loop located between transmembrane segments 2 and 3. J Biol Chem. 2002;277:30852–30858. doi: 10.1074/jbc.M202418200
  • Singh AK, McGoldrick LL, Twomey EC, et al. Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6. Sci Adv. 2018;4(8):eaau6088. doi: 10.1126/sciadv.aau6088
  • Khattar V, Wang L, Peng J-B. Calcium selective channel TRPV6: Structure, function, and Implications in health and disease. Gene. 2022;817:146192. doi: 10.1016/j.gene.2022.146192
  • Yelshanskaya MV, Nadezhdin KD, Kurnikova MG, et al. Structure and function of the calcium‐selective TRP channel TRPV6. Journal Of Physiology. 2021;599(10):2673–2697. doi: 10.1113/JP279024
  • Walker V, Vuister GW. Biochemistry and pathophysiology of the transient potential receptor vanilloid 6 (TRPV6) calcium channel. Adv Clin Chem. 2023;113:43–100. doi: 10.1016/bs.acc.2022.11.002
  • Peng JB, Chen XZ, Berger UV, et al. Human calcium transport protein CaT1. Biochem Biophys Res Commun pii. 2000;278:326–332. doi: 10.1006/bbrc.2000.3716
  • Hirnet D, Olausson J, Fecher-Trost C, et al. The TRPV6 gene, cDNA and protein. Cell Calcium. 2003;33(5–6):509–518. doi: 10.1016/S0143-4160(03)00066-6
  • Semenova SB, Vassilieva IO, Fomina AF, et al. Endogenous expression of TRPV5 and TRPV6 calcium channels in human leukemia K562 cells. Am J Physiol Cell Physiol. 2009;296(5):C1098–1104. pii. doi: 10.1152/ajpcell.00435.200800435.2008.
  • Giusti L, Cetani F, Da Valle Y, et al. First evidence of TRPV5 and TRPV6 channels in human parathyroid glands: possible involvement in neoplastic transformation. J Cell Mol Med. 2014;18(10):1944–1952. doi: 10.1111/jcmm.12372
  • Wartenberg P, Lux F, Busch K, et al. A TRPV6 expression atlas for the mouse. Cell Calcium. 2021;100:102481. doi: 10.1016/j.ceca.2021.102481
  • Wissenbach U, Niemeyer BA, Fixemer T, et al. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J Biol Chem. 2001;276(22):19461–19468. doi: 10.1074/jbc.M009895200
  • Peng JB, Chen X-Z, Berger UV, et al. Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem. 1999;274(32):22739–22746. doi: 10.1074/jbc.274.32.22739
  • Bianco SD, Peng J-B, Takanaga H, et al. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J Bone Mineral Res. 2007;22(2):274–285. doi: 10.1359/jbmr.061110
  • Suzuki Y, Kovacs CS, Takanaga, H et al. Calcium channel TRPV6 is involved in murine maternal–fetal calcium transport. J Bone Mineral Res. 2008;23:1249–1256. doi: 10.1359/jbmr.080314
  • Weissgerber P, Kriebs U, Tsvilovskyy V, et al. Excision of Trpv6 gene leads to severe defects in epididymal Ca2+ absorption and male fertility much like single D541A pore mutation. J Biol Chem. 2012;287(22):17930–17941. doi: 10.1074/jbc.M111.328286
  • Weissgerber P, Kriebs U, Tsvilovskyy V, et al. Male fertility depends on Ca2+ absorption by TRPV6 in epididymal epithelia. Sci Signaling. 2011;4(171):ra27–ra27. doi: 10.1126/scisignal.2001791
  • Lieben L, Benn BS, Ajibade D, et al. Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis. Bone. 2010;47(2):301–308. doi: 10.1016/j.bone.2010.04.595
  • Wangemann P, Nakaya K, Wu T, et al. Loss of cochlear HCO3− secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model. Am J Physiol Renal Physiol. 2007;292(5):F1345–F1353. doi: 10.1152/ajprenal.00487.2006
  • Huybers S, Apostolaki M, van der Eerden BC, et al. Murine TNF ΔARE Crohn’s disease model displays diminished expression of intestinal Ca2+ transporters. Inflamm Bowel Dis. 2008;14:803–811. doi: 10.1002/ibd.20385
  • Wu G, Zhang W, Na T, et al. Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease. Am J Physiol Cell Physiol. 2012;302(10):C1479–C1491. doi: 10.1152/ajpcell.00277.2011
  • Yang SS, Lo Y-F, Yu I-S, et al. Generation and analysis of the thiazide‐sensitive Na+‐Cl− cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome. Human Mutation. 2010;31(12):1304–1315. doi: 10.1002/humu.21364
  • Frick KK, Asplin JR, Favus MJ, et al. Increased biological response to 1,25(OH)2D3 in genetic hypercalciuric stone-forming rats. Am J Physiol Renal Physiol. 2013;304(6):F718–F726. doi: 10.1152/ajprenal.00645.2012
  • Haché S, Takser L, LeBellego F, et al. Alteration of calcium homeostasis in primary preeclamptic syncytiotrophoblasts: effect on calcium exchange in placenta. J Cell Mol Med. 2011;15(3):654–667. doi: 10.1111/j.1582-4934.2010.01039.x
  • Suzuki Y, Chitayat D, Sawada H, et al. TRPV6 variants interfere with maternal-fetal calcium transport through the placenta and cause transient neonatal hyperparathyroidism. Am J Hum Genet. 2018;102(6):1104–1114. doi: 10.1016/j.ajhg.2018.04.006
  • Burren CP, Caswell R, Castle B, et al. TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton. Am J Med Genet A. 2018;176(9):1950–1955. doi: 10.1002/ajmg.a.40484
  • Nett V, Erhardt N, Wyatt A, et al. Human TRPV6-pathies caused by gene mutations. Biochim Biophys Acta. 2021;1865(6):129873. doi: 10.1016/j.bbagen.2021.129873
  • Masamune A, Kotani H, Sörgel FL, et al. Variants that affect function of calcium channel TRPV6 are associated with early-onset chronic pancreatitis. Gastroenterology. 2020;158(6):1626–1641. e1628. doi: 10.1053/j.gastro.2020.01.005
  • Suzuki Y, Sawada H, Tokumasu T, et al. Novel TRPV6 mutations in the spectrum of transient neonatal hyperparathyroidism. J Physiol Sci. 2020;70(1):1–10. doi: 10.1186/s12576-020-00761-2
  • Yamashita S, Mizumoto H, Sawada H, et al. TRPV6 gene mutation in a dizygous twin with transient neonatal hyperparathyroidism. J Endocr Soc. 2019;3(3):602–606. doi: 10.1210/js.2018-00374
  • Zou WB, Wang Y-C, Ren X-L, et al. TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population. Human Mutation. 2020;41(8):1351–1357. doi: 10.1002/humu.24032
  • Stewart JM. TRPV6 as a target for cancer therapy. J Cancer. 2020;11(2):374. doi: 10.7150/jca.31640
  • Peng J-B, Zhuang L, Berger UV, et al. CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun. 2001;282(3):729–734. doi: 10.1006/bbrc.2001.4638
  • Fixemer T, Wissenbach U, Flockerzi V, et al. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression. Oncogene. 2003;22(49):7858–7861. doi: 10.1038/sj.onc.1206895
  • Zhuang L, Peng J-B, Tou L, et al. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest. 2002;82(12):1755–1764. doi: 10.1097/01.LAB.0000043910.41414.E7
  • Peleg S, Sellin JH, Wang Y, et al. Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium. Am J Physiol Gastrointest Liver Physiol. 2010;299(3):G593–G601. doi: 10.1152/ajpgi.00193.2010
  • Xu X, Li N, Wang Y, et al. Calcium channel TRPV6 promotes breast cancer metastasis by NFATC2IP. Cancer Lett. 2021;519:150–160. doi: 10.1016/j.canlet.2021.07.017
  • Peters AA, Simpson PT, Bassett JJ, et al. Calcium channel TRPV6 as a potential therapeutic target in Estrogen receptor–Negative breast Cancer Characterization of TRPV6 in breast cancer. Mol Cancer Ther. 2012;11(10):2158–2168. doi: 10.1158/1535-7163.MCT-11-0965
  • Dhennin-Duthille I, Gautier M, Faouzi M, et al. High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters. Cell Physiol Biochem. 2011;28(5):813–822. doi: 10.1159/000335795
  • Francis-Lyon PA, Malik F, Cheng X, et al. TRPV6 as a putative genomic susceptibility locus influencing racial disparities in cancer. Cancer Prev Res. 2020;13(5):423–428. doi: 10.1158/1940-6207.CAPR-19-0351
  • Haverstick DM, Heady TN, Macdonald TL, et al. Inhibition of human prostate cancer proliferation in vitro and in a mouse model by a compound synthesized to block Ca2+ entry. Cancer Res. 2000;60(4):1002–1008.
  • Landowski CP, Bolanz KA, Suzuki Y, et al. Chemical inhibitors of the calcium entry channel TRPV6. Pharm Res. 2011;28(2):322–330. doi: 10.1007/s11095-010-0249-9
  • Kovacs G, Montalbetti N, Simonin A, et al. Inhibition of the human epithelial calcium channel TRPV6 by 2-aminoethoxydiphenyl borate (2-APB). Cell Calcium. 2012;52(6):468–480. doi: 10.1016/j.ceca.2012.08.005
  • Hofer A, Kovacs G, Zappatini A, et al. Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport. Bioorg Med Chem. 2013;21(11):3202–3213. pii. doi: 10.1016/j.bmc.2013.03.037S0968-0896(13)00253-8
  • Simonin C, Awale M, Brand M, et al. Optimization of TRPV6 calcium channel inhibitors using a 3D Ligand-based Virtual Screening Method. Angew Chem Int Ed Engl. 2015;54(49):14748–14752. doi: 10.1002/anie.201507320
  • Cunha MR, Bhardwaj R, Carrel AL, et al. Natural Product Inspired Optimization of a selective TRPV6 calcium channel inhibitor. RSC Med Chem. 2020;11:1032–1040. doi: 10.1039/D0MD00145G
  • Cunha MR, Bhardwaj R, Lindinger S, et al. Photoswitchable inhibitor of the calcium channel TRPV6. ACS Med Chem Lett. 2019;10(9):1341–1345. doi: 10.1021/acsmedchemlett.9b00298
  • Fu S, Hirte H, Welch S, et al. First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors. Invest New Drugs pii. 2017;35:324–333. doi: 10.1007/s10637-017-0438-z
  • Xue H, Wang Y, MacCormack TJ, et al. Inhibition of transient receptor potential vanilloid 6 channel, elevated in human ovarian cancers, reduces tumour growth in a xenograft model. J Cancer. 2018;9(17):3196–3207. doi: 10.7150/jca.20639
  • Bowen CV, DeBay D, Ewart HS, et al. In vivo detection of human TRPV6-rich tumors with anti-cancer peptides derived from soricidin. PLoS One. 2013;8(3):e58866. doi: 10.1371/journal.pone.0058866
  • Saotome K, Singh AK, Yelshanskaya MV, et al. Crystal structure of the epithelial calcium channel TRPV6. Nature. 2016;534(7608):506–511. doi: 10.1038/nature17975
  • McGoldrick LL, Singh AK, Saotome K, et al. Opening of the human epithelial calcium channel TRPV6. Nature. 2018;553(7687):233–237. doi: 10.1038/nature25182
  • Bhardwaj R, Lindinger S, Neuberger A, et al. Inactivation-mimicking block of the epithelial calcium channel TRPV6. Sci Adv. 2020;6(48):eabe1508. doi: 10.1126/sciadv.abe1508
  • Neuberger A, Nadezhdin KD, Sobolevsky AI. Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole. Nat Commun. 2021;12(1):1–10. doi: 10.1038/s41467-021-26608-x
  • Neuberger A, Trofimov YA, Yelshanskaya MV, et al. Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein. Nat Commun. 2023;14(1):1–13. doi: 10.1038/s41467-023-38352-5
  • Long SB, Tao X, Campbell EB, et al. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature. 2007;450(7168):376–382. doi: 10.1038/nature06265
  • Singh AK, Saotome K, Sobolevsky AI. Swapping of transmembrane domains in the epithelial calcium channel TRPV6. Sci Rep. 2017;7(1):1–10. doi: 10.1038/s41598-017-10993-9
  • Yelshanskaya MV, Sobolevsky AI. Ligand-binding sites in vanilloid-Subtype TRP channels. Front Pharmacol. 2022;13:900623. doi: 10.3389/fphar.2022.900623
  • Lee J, Cha SK, Sun TJ, et al. PIP2 activates TRPV5 and releases its inhibition by intracellular Mg2+. J Gen Physiol. 2005;126(5):439–451. doi: 10.1085/jgp.200509314
  • Hughes TET, Pumroy RA, Yazici AT, et al. Structural insights on TRPV5 gating by endogenous modulators. Nat Commun. 2018;9:4198. doi: 10.1038/s41467-018-06753-6
  • Neuberger A, Nadezhdin KD, Sobolevsky AI. Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole. Nat Commun. 2021;12(1):6284. doi: 10.1038/s41467-021-26608-x
  • Fluck EC, Yazici AT, Rohacs T, et al. Structural basis of TRPV5 regulation by physiological and pathophysiological modulators. Cell Rep. 2022;39(4):110737. doi: 10.1016/j.celrep.2022.110737
  • Fathizadeh A, Senning E, Elber R. Impact of the Protonation state of phosphatidylinositol 4,5-bisphosphate (PIP2) on the binding Kinetics and Thermodynamics to transient receptor potential vanilloid (TRPV5): A Milestoning study. J Phys Chem B. 2021;125(33):9547–9556. doi: 10.1021/acs.jpcb.1c04052
  • Lee BH, De Jesus Perez JJ, Moiseenkova-Bell V, et al. Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A. Nat Commun. 2023;14(1):5883. doi: 10.1038/s41467-023-41577-z
  • Bate N, Caves RE, Skinner SP, et al. A novel mechanism for calmodulin-dependent inactivation of transient receptor potential vanilloid 6. Biochem. 2018;57(18):2611–2622. doi: 10.1021/acs.biochem.7b01286
  • Kovalevskaya NV, Bokhovchuk FM, Vuister GW. The TRPV5/6 calcium channels contain multiple calmodulin binding sites with differential binding properties. J Struct Funct Genomics. 2012;13:91–100. doi: 10.1007/s10969-012-9128-4
  • de Groot T, Kovalevskaya NV, Verkaart S, et al. Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone. Mol Cell Biol. 2011;31(14):2845–2853. doi: 10.1128/MCB.01319-10
  • Holakovska B, Grycova L, Bily J, et al. Characterization of calmodulin binding domains in TRPV2 and TRPV5 C-tails. Amino Acids. 2011;40(2):741–748. doi: 10.1007/s00726-010-0712-2
  • Dang S, Van Goor, MK, Asarnow, D et al. Structural insight into TRPV5 channel function and modulation. Proceedings of the National Academy of Sciences 116, 8869–8878. 2019.
  • Zuidscherwoude M, van Goor MK, Roig SR, et al. Functional basis for calmodulation of the TRPV5 calcium channel. J Physiol. 2023;601(4):859–878. doi: 10.1113/JP282952
  • van der Wijst J, Leunissen EH, Blanchard MG, et al. A gate hinge controls the epithelial calcium channel TRPV5. Sci Rep. 2017;7(1):45489. doi: 10.1038/srep45489
  • Nowak L, Bregestovski P, Ascher P, et al. Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984;307(5950):462–465. doi: 10.1038/307462a0
  • Sobolevsky AI, Yelshansky MV. The trapping block of NMDA receptor channels in acutely isolated rat hippocampal neurones. J Physiol. 2000;526(3):493–506. doi: 10.1111/j.1469-7793.2000.t01-2-00493.x
  • Suh BC, Hille B. Electrostatic interaction of internal Mg2+ with membrane PIP2 Seen with KCNQ K+ channels. J Gen Physiol. 2007;130(3):241–256. doi: 10.1085/jgp.200709821
  • Liao M, Cao E, Julius D, et al. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature. 2013;504(7478):107–112. doi: 10.1038/nature12822
  • Cao E, Liao M, Cheng Y, et al. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature. 2013;504(7478):113–118. doi: 10.1038/nature12823
  • Neuberger A, Oda M, Nikolaev YA, et al. Human TRPV1 structure and inhibition by the analgesic SB-366791. Nat Commun. 2023;14(1):2451. doi: 10.1038/s41467-023-38162-9
  • Singh AK, Saotome K, McGoldrick LL, et al. Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB. Nat Commun. 2018;9(1):1–11. doi: 10.1038/s41467-018-04828-y
  • Clarke MJ. Ruthenium metallopharmaceuticals. Coordin Chem Rev. 2002;232(1–2):69–93. doi: 10.1016/S0010-8545(02)00025-5
  • Tapia R, Velasco I. Ruthenium red as a tool to study calcium channels, neuronal death and the function of neural pathways. Neurochem Int. 1997;30(2):137–147. doi: 10.1016/s0197-0186(96)00056-3
  • Yamada K. Dual staining of some sulfated mucopolysaccharides with alcian blue (pH 1.0) and ruthenium red (pH 2.5). Histochemie. 1970;23(1):13–20. doi: 10.1007/BF00309485
  • Pope L, Lolicato M, Minor DL Jr. Polynuclear ruthenium Amines inhibit K2P channels via a “Finger in the Dam” mechanism. Cell Chem Biol. 2020;27(5):511–524.e4. doi: 10.1016/j.chembiol.2020.01.011
  • Choi W, Clemente N, Sun W, et al. The structures and gating mechanism of human calcium homeostasis modulator 2. Nature. 2019;576(7785):163–167. doi: 10.1038/s41586-019-1781-3
  • Nelson AM, Moayedi Y, Greenberg SA et al. 2-APB arrests human keratinocyte proliferation and inhibits cutaneous squamous cell carcinoma in vitro. bioRxiv. 2018;249821. doi:10.1101/249821.
  • Maruyama T, Kanaji T, Nakade S, et al. 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4, 5)P3-induced Ca2+ release. The Journal Of Biochemistry. 1997;122(3):498–505. doi: 10.1093/oxfordjournals.jbchem.a021780
  • Togashi K, Inada H, Tominaga M. Inhibition of the transient receptor potential cation channel TRPM2 by 2‐aminoethoxydiphenyl borate (2‐APB). Br J Pharmacol. 2008;153(6):1324–1330. doi: 10.1038/sj.bjp.0707675
  • Lievremont J-P, Bird GS, Putney JW. Mechanism of inhibition of TRPC cation channels by 2-aminoethoxydiphenylborane. Mol Pharmacol. 2005;68(3):758–762. doi: 10.1124/mol.105.012856
  • Chokshi R, Fruasaha P, Kozak JA. 2-aminoethyl diphenyl borinate (2-APB) inhibits TRPM7 channels through an intracellular acidification mechanism. Channels. 2012;6(5):362–369. doi: 10.4161/chan.21628
  • Thienpont D, Van Cutsem J, Van Nueten J, et al. Biological and toxicological properties of econazole, a broad-spectrum antimycotic. Arzneimittel-forschung. 1975;25(2):224–230.
  • Wyler R, Murbach A, Möhl H. An imidazole derivative (econazole) as an antifungal agent in cell culture systems. In Vitro. 1979;15(10):745–750. doi: 10.1007/BF02618300
  • Heel R, Brogden R, Speight T, et al. Econazole: a review of its antifungal activity and therapeutic efficacy. Drugs. 1978;16(3):177–201. doi: 10.2165/00003495-197816030-00001
  • Schwarz EC, Wissenbach U, Niemeyer BA, et al. TRPV6 potentiates calcium-dependent cell proliferation. Cell Calcium. 2006;39(2):163–173. doi: 10.1016/j.ceca.2005.10.006
  • Nilius B, Prenen J, Vennekens R, et al. Pharmacological modulation of monovalent cation currents through the epithelial Ca2+ channel ECaC1. Br J Pharmacol. 2001;134(3):453–462. doi: 10.1038/sj.bjp.0704272
  • Neuberger A, Oraiopoulos N, Drakeman DL. In drug Discovery Today. 2019;24(1):1–3.
  • Neuberger A, Oraiopoulos N, Drakeman DL. Lemons, or squeezed for resources? Information symmetry and asymmetric resources in biotechnology. Front Pharmacol. 2017;8:338. doi: 10.3389/fphar.2017.00338
  • Yelshanskaya MV, Sobolevsky AI. Ligand-binding sites in vanilloid-Subtype TRP channels. Front Pharmacol. 2022;13. doi: 10.3389/fphar.2022.900623
  • Bhattaram VA, Graefe U, Kohlert C, et al. Pharmacokinetics and bioavailability of herbal medicinal products. Phytomedicine. 2002;9:1–33. doi: 10.1078/1433-187X-00210
  • Neuberger A, Nadezhdin KD, Zakharian E, et al. Structural mechanism of TRPV3 channel inhibition by the plant‐derived coumarin osthole. EMBO Rep. 2021;22(11):e53233. doi: 10.15252/embr.202153233
  • Neuberger A, Trofimov YA, Yelshanskaya MV, et al. Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin. Nat Commun. 2023. forthcomingearly August. doi: 10.1038/s41467-023-40362-2.
  • Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chemistry & Biodiversity. 2007;4(8):1614–1648. doi: 10.1002/cbdv.200790144
  • Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci. 2022;9(4):413–430.
  • Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci. 2019;11:487. doi:10.3389/fnmol.2018.00487
  • Pumroy RA, Protopopova AD, Fricke TC, et al. Structural insights into TRPV2 activation by small molecules. Nat Commun. 2022;13(1):1–12. doi: 10.1038/s41467-022-30083-3
  • Pumroy RA, Samanta A, Liu Y, et al. Molecular mechanism of TRPV2 channel modulation by cannabidiol. Elife. 2019;8:e48792. doi: 10.7554/eLife.48792
  • Neuberger A, Nadezhdin KD, Sobolevsky AI. Structural mechanism of TRPV3 channel inhibition by the anesthetic dyclonine. Nat Commun. 2022;13(1):1–9. doi: 10.1038/s41467-022-30537-8
  • Janssens A, Silvestri C, Martella A, et al. Δ9-tetrahydrocannabivarin impairs epithelial calcium transport through inhibition of TRPV5 and TRPV6. Pharmacol Res. 2018;136:83–89. DOI:10.1016/j.phrs.2018.08.021
  • Dixon RA, Ferreira DG. Phytochemistry. 2002;60:205–211. doi: 10.1016/S0031-9422(02)00116-4
  • Banerjee S, Li Y, Wang Z, et al. Multi-targeted therapy of cancer by genistein. Cancer Lett. 2008;269(2):226–242. doi: 10.1016/j.canlet.2008.03.052
  • Bhagwat S, Haytowitz DB, Holden JM. USDA database for the isoflavone content of selected foods, release 2.0. Maryland: US Department Of Agriculture. 2008;15:1–67.
  • Liggins J, Bluck LJC, Runswick S, et al. Daidzein and genistein contents of vegetables. British Journal Of Nutrition. 2000;84(5):717–725. doi: 10.1017/S0007114500002075
  • Pintova S, Dharmupari S, Moshier E, et al. Genistein combined with FOLFOX or FOLFOX–Bevacizumab for the treatment of metastatic colorectal cancer: Phase I/II pilot study. Cancer Chemother Pharmacol. 2019;84:591–598. doi: 10.1007/s00280-019-03886-3
  • Pavese JM, Farmer RL, Bergan RC. Inhibition of cancer cell invasion and metastasis by genistein. Cancer Metast Rev. 2010;29(3):465–482. doi: 10.1007/s10555-010-9238-z
  • Huang X, Chen S, Xu L, et al. Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res. 2005;65(8):3470–3478. doi: 10.1158/0008-5472.CAN-04-2807
  • Lakshman M, Xu L, Ananthanarayanan V, et al. Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res. 2008;68(6):2024–2032. doi: 10.1158/0008-5472.CAN-07-1246
  • Xu L, Bergan RC. Genistein inhibits matrix metalloproteinase type 2 activation and prostate cancer cell invasion by blocking the transforming growth factor β-mediated activation of mitogen-activated protein kinase-activated protein kinase 2-27-kDa heat shock protein pathway. Mol Pharmacol. 2006;70:869–877. doi: 10.1124/mol.106.023861
  • Xu L, Ding Y, Catalona WJ, et al. MEK4 function, genistein treatment, and invasion of human prostate cancer cells. JNCI. 2009;101(16):1141–1155. doi: 10.1093/jnci/djp227
  • Scholar EM, Toews ML. Inhibition of invasion of murine mammary carcinoma cells by the tyrosine kinase inhibitor genistein. Cancer Lett. 1994;87(2):159–162. doi: 10.1016/0304-3835(94)90217-8
  • Li Y, Sarkar FH. Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3 prostate cancer cells treated with genistein. Cancer Lett. 2002;186(2):157–164. doi: 10.1016/S0304-3835(02)00349-X
  • Nakamura A, Aizawa J, Sakayama K, et al. Genistein inhibits cell invasion and motility by inducing cell differentiation in murine osteosarcoma cell line LM8. BMC Cell Biol. 2012;13(1):1–10. doi: 10.1186/1471-2121-13-24
  • Fritz WA, Coward L, Wang J, et al. Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis. 1998;19:2151–2158. doi:10.1093/carcin/19.12.2151
  • Lamartiniere CA. Protection against breast cancer with genistein: a component of soy. Am J Clin Nutr. 2000;71(6):1705S–1707S. doi: 10.1093/ajcn/71.6.1705S
  • Yanagihara K, Ito A, Toge T, et al. Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res. 1993;53:5815–5821.
  • Lee H, Lee J, Gourley L, et al. Dietary effects on breast-cancer risk in Singapore. Lancet. 1991;337(8751):1197–1200. doi: 10.1016/0140-6736(91)92867-2
  • Uckun F, Evans WE, Forsyth CJ, et al. Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases. Science. 1995;267(5199):886–891. doi: 10.1126/science.7531365
  • Harper CE, Cook LM, Patel BB, et al. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV‐40 tag rats. Prostate. 2009;69(15):1668–1682. doi: 10.1002/pros.21017
  • Shafiee G, Saidijam M, Tayebinia H, et al. Beneficial effects of genistein in suppression of proliferation, inhibition of metastasis, and induction of apoptosis in PC3 prostate cancer cells. Arch Physiol Biochem. 2022;128(3):694–702. doi: 10.1080/13813455.2020.1717541
  • Imai-Sumida M, Dasgupta P, Kulkarni P, et al. Genistein represses HOTAIR/chromatin remodeling pathways to suppress kidney cancer. Cell Physiol Biochem. 2020;54:53.
  • Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-kB activation in prostate cancer cells. Nutr Cancer. 1999;35(2):167–174. doi: 10.1207/S15327914NC352_11
  • Sarkar FH, Li Y. Mechanisms of cancer chemoprevention by soy isoflavone genistein. Cancer Metast Rev. 2002;21(3/4):265–280. doi: 10.1023/A:1021210910821
  • Lamartiniere CA, Moore J, Holland M, et al. Neonatal genistein chemoprevents mammary cancer. Proceedings of the Society for Experimental Biology and Medicine 208, 120–123 (1995).
  • Gossner G, CHOI M, TAN L, et al. Genistein-induced apoptosis and autophagocytosis in ovarian cancer cells. Gynecol Oncol. 2007;105(1):23–30. doi: 10.1016/j.ygyno.2006.11.009
  • Pagliacci M, Smacchia M, Migliorati G, et al. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer. 1994;30(11):1675–1682. doi: 10.1016/0959-8049(94)00262-4
  • Lamartiniere CA, Moore JB, Brown NM, et al. Genistein suppresses mammary cancer in rats. Carcinogenesis. 1995;16(11):2833–2840. doi: 10.1093/carcin/16.11.2833
  • Li Y, Sarkar FH. Gene expression profiles of genistein-treated PC3 prostate cancer cells. J Nutr. 2002;132(12):3623–3631. doi: 10.1093/jn/132.12.3623
  • Cappelletti V, Fioravanti L, Miodini P, et al. Genistein blocks breast cancer cells in the G2M phase of the cell cycle. J Cell Biochem. 2000;79(4):594–600. doi: 10.1002/1097-4644(20001215)79:4<594:AID-JCB80>3.0.CO;2-4
  • Chen W-F, Huang M-H, Tzang C-H, et al. Inhibitory actions of genistein in human breast cancer (MCF-7) cells. Biochim Biophys Acta Mol Basis Dis. 2003;1638:187–196. doi: 10.1016/S0925-4439(03)00082-6
  • Lee J-Y, Kim HS, Song Y-S. Genistein as a potential anticancer agent against ovarian cancer. J Tradit Complement Med. 2012;2(2):96–104. doi: 10.1016/S2225-4110(16)30082-7
  • Lian F, Li Y, Bhuiyan M, et al. H. p53-independent apoptosis induced by genistein in lung cancer cells. Nutr Cancer. 1999;33(2):125–131. doi: 10.1207/S15327914NC330202
  • Ma J, Cheng L, Liu H, et al. Genistein down-regulates miR-223 expression in pancreatic cancer cells. Curr Drug Targets. 2013;14(10):1150–1156. doi: 10.2174/13894501113149990187
  • Murrill WB, Brown NM, Zhang JX, et al. Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis. 1996;17:1451–1458. doi: 10.1093/carcin/17.7.1451
  • Yu Z, Li W, Liu F. Inhibition of proliferation and induction of apoptosis by genistein in colon cancer HT-29 cells. Cancer Lett. 2004;215(2):159–166. doi: 10.1016/j.canlet.2004.06.010
  • Gong L, Li Y, Nedeljkovic-Kurepa A, et al. Inactivation of NF-κB by genistein is mediated via Akt signaling pathway in breast cancer cells. Oncogene. 2003;22(30):4702–4709. doi: 10.1038/sj.onc.1206583
  • Wang J, Eltoum I-E, Lamartiniere CA. Dietary genistein suppresses chemically induced prostate cancer in Lobund–Wistar rats. Cancer Lett. 2002;186(1):11–18. doi: 10.1016/S0304-3835(01)00811-4
  • Merz-Demlow BE, Duncan AM, Wangen KE, et al. Soy isoflavones improve plasma lipids in normocholesterolemic, premenopausal women. Am J Clin Nutr. 2000;71(6):1462–1469. doi: 10.1093/ajcn/71.6.1462
  • Peluso MR, Winters TA, Shanahan MF, et al. A cooperative interaction between soy protein and its isoflavone-enriched fraction lowers hepatic lipids in male obese Zucker rats and reduces blood platelet sensitivity in male Sprague-Dawley rats. J Nutr. 2000;130(9):2333–2342. doi: 10.1093/jn/130.9.2333
  • Hwang J, Hodis HN, Sevanian A. Soy and alfalfa phytoestrogen extracts become potent low-density lipoprotein antioxidants in the presence of acerola cherry extract. J Agric Food Chemistry. 2001;49(1):308–314. doi: 10.1021/jf0007028
  • File SE, Jarrett N, Fluck E, et al. Eating soya improves human memory. Psychopharmacology. 2001;157(4):430–436. doi: 10.1007/s002130100845
  • Alekel DL, Germain AS, Peterson CT, et al. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr. 2000;72(3):844–852. doi: 10.1093/ajcn/72.3.844
  • Phetnoo N, Werawatganon D, Siriviriyakul P. Genistein could have a therapeutic potential for gastrointestinal diseases. Thai J Gastroenterol. 2013;14:120–125.
  • Marini H, Minutoli L, Polito F, et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann internal med. 2007;146(12):839–847. doi: 10.7326/0003-4819-146-12-200706190-00005
  • Li B, Yu S. Genistein prevents bone resorption diseases by inhibiting bone resorption and stimulating bone formation. Biol Pharm Bull. 2003;26(6):780–786. doi: 10.1248/bpb.26.780
  • Lu R, Zheng Z, Yin Y, et al. Genistein prevents bone loss in type 2 diabetic rats induced by streptozotocin. Food & Nutrition Research. 2020;64. doi: 10.29219/fnr.v64.3666
  • Albertazzi P. Purified phytoestrogens in postmenopausal bone health: is there a role for genistein? Climacteric. 2002;5(2):190–196. doi: 10.1080/cmt.5.2.190.196
  • Pavese JM, Krishna SN, Bergan RC. Genistein inhibits human prostate cancer cell detachment, invasion, and metastasis. Am J Clin Nutr. 2014;100:431S–436S. doi:10.3945/ajcn.113.071290
  • Squadrito F, Marini H, Bitto A, et al. Genistein in the metabolic syndrome: results of a randomized clinical trial. J Clin Endocrinol Metab. 2013;98(8):3366–3374. doi: 10.1210/jc.2013-1180
  • Smart OS, Neduvelil JG, Wang X, et al. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J Mol Graph. 1996;14:354–360. doi:10.1016/S0263-7855(97)00009-X