Bithionol
Bithionol, also known as Lorothidol and CP-3438, is an ENPP2 protein inhibitor used to treat hepatic fascioliasis. Bithionol is a clinically approved anti-parasitic drug used as an anti-ovarian cancer drug. Bithionol exhibits cytotoxic effects on various ovarian cancer cell lines regardless of their sensitivities to cisplatin. Cell death appears to be via caspases mediated apoptosis. The mechanisms of action appear to be partly via cell cycle arrest, reactive oxygen species generation and inhibition of autotaxin.
1: Florent RL, Becker JA, Powell MD. In vitro toxicity of bithionol and bithionol sulphoxide to Neoparamoeba spp., the causative agent of amoebic gill disease (AGD). Dis Aquat Organ. 2010 Sep 17;91(3):257-62. doi: 10.3354/dao02269. PubMed PMID: 21133325.
2: Florent RL, Becker J, Powell MD. Further development of bithionol therapy as a treatment for amoebic gill disease in Atlantic salmon, Salmo salar L. J Fish Dis. 2009 May;32(5):391-400. doi: 10.1111/j.1365-2761.2008.01001.x. PubMed PMID: 19243491.
3: Ayyagari VN, Brard L. Bithionol inhibits ovarian cancer cell growth in vitro - studies on mechanism(s) of action. BMC Cancer. 2014 Feb 4;14:61. doi: 10.1186/1471-2407-14-61. PubMed PMID: 24495391; PubMed Central PMCID: PMC3922745.
4: Sanada Y, Senba H, Mochizuki R, Arakaki H, Gotoh T, Fukumoto S, Nagahata H. Evaluation of marked rise in fecal egg output after bithionol administration to horse and its application as a diagnostic marker for equine Anoplocephala perfoliata infection. J Vet Med Sci. 2009 May;71(5):617-20. PubMed PMID: 19498288.
5: Reid L, Khammo N, Clothier RH. An evaluation of the effects of photoactivation of bithionol, amiodarone and chlorpromazine on human keratinocytes in vitro. Altern Lab Anim. 2007 Oct;35(5):471-85. PubMed PMID: 18001169.
6: Florent RL, Becker JA, Powell MD. Evaluation of bithionol as a bath treatment for amoebic gill disease caused by Neoparamoeba spp. Vet Parasitol. 2007 Mar 31;144(3-4):197-207. PubMed PMID: 17129675.
7: Matsubara K, Sanoh S, Ohta S, Kitamura S, Sugihara K, Fujimoto N. An improved thyroid hormone reporter assay to determine the thyroid hormone-like activity of amiodarone, bithionol, closantel and rafoxanide. Toxicol Lett. 2012 Jan 5;208(1):30-5. doi: 10.1016/j.toxlet.2011.10.004. PubMed PMID: 22015988.
8: Sakamoto M, Takeba K, Sasamoto T, Kusano T, Hayashi H, Kanai S, Kanda M, Nagayama T. Determination of bithionol, bromophen, nitroxynil, oxyclozanide, and tribromsalan in milk with liquid chromatography coupled with tandem mass spectrometry. J AOAC Int. 2010 Jul-Aug;93(4):1340-6. PubMed PMID: 20922970.
9: Kleinboelting S, Ramos-Espiritu L, Buck H, Colis L, van den Heuvel J, Glickman JF, Levin LR, Buck J, Steegborn C. Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site. J Biol Chem. 2016 Apr 29;291(18):9776-84. doi: 10.1074/jbc.M115.708255. PubMed PMID: 26961873; PubMed Central PMCID: PMC4850313.
10: Reid L, Clothier RH, Khammo N. Hydrogen peroxide induced stress in human keratinocytes and its effect on bithionol toxicity. Toxicol In Vitro. 2001 Aug-Oct;15(4-5):441-5. PubMed PMID: 11566576.
11: Leonardi W, Zilbermintz L, Cheng LW, Zozaya J, Tran SH, Elliott JH, Polukhina K, Manasherob R, Li A, Chi X, Gharaibeh D, Kenny T, Zamani R, Soloveva V, Haddow AD, Nasar F, Bavari S, Bassik MC, Cohen SN, Levitin A, Martchenko M. Bithionol blocks pathogenicity of bacterial toxins, ricin, and Zika virus. Sci Rep. 2016 Sep 30;6:34475. doi: 10.1038/srep34475. PubMed PMID: 27686742; PubMed Central PMCID: PMC5043268.
12: Ayyagari VN, Johnston NA, Brard L. Assessment of the antitumor potential of Bithionol in vivo using a xenograft model of ovarian cancer. Anticancer Drugs. 2016 Jul;27(6):547-59. doi: 10.1097/CAD.0000000000000364. PubMed PMID: 27058706; PubMed Central PMCID: PMC5053334.
13: Eleuteri S, Di Giovanni S, Rockenstein E, Mante M, Adame A, Trejo M, Wrasidlo W, Wu F, Fraering PC, Masliah E, Lashuel HA. Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease. Neurobiol Dis. 2015 Feb;74:144-57. doi: 10.1016/j.nbd.2014.08.017. PubMed PMID: 25173807; PubMed Central PMCID: PMC4323687.
14: Kodama K. [Human fascioliasis: comparison of a fasciolicidal effect of bithionol and praziquantel]. Kansenshogaku Zasshi. 1997 Nov;71(11):1162-7. Review. Japanese. PubMed PMID: 9455057.
15: Hozumi H, Hokari R, Kurihara C, Narimatsu K, Sato H, Sato S, Ueda T, Higashiyama M, Okada Y, Watanabe C, Komoto S, Tomita K, Kawaguchi A, Nagao S, Miura S. Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration. Lab Invest. 2013 May;93(5):508-19. doi: 10.1038/labinvest.2013.45. PubMed PMID: 23478591.
2: Florent RL, Becker J, Powell MD. Further development of bithionol therapy as a treatment for amoebic gill disease in Atlantic salmon, Salmo salar L. J Fish Dis. 2009 May;32(5):391-400. doi: 10.1111/j.1365-2761.2008.01001.x. PubMed PMID: 19243491.
3: Ayyagari VN, Brard L. Bithionol inhibits ovarian cancer cell growth in vitro - studies on mechanism(s) of action. BMC Cancer. 2014 Feb 4;14:61. doi: 10.1186/1471-2407-14-61. PubMed PMID: 24495391; PubMed Central PMCID: PMC3922745.
4: Sanada Y, Senba H, Mochizuki R, Arakaki H, Gotoh T, Fukumoto S, Nagahata H. Evaluation of marked rise in fecal egg output after bithionol administration to horse and its application as a diagnostic marker for equine Anoplocephala perfoliata infection. J Vet Med Sci. 2009 May;71(5):617-20. PubMed PMID: 19498288.
5: Reid L, Khammo N, Clothier RH. An evaluation of the effects of photoactivation of bithionol, amiodarone and chlorpromazine on human keratinocytes in vitro. Altern Lab Anim. 2007 Oct;35(5):471-85. PubMed PMID: 18001169.
6: Florent RL, Becker JA, Powell MD. Evaluation of bithionol as a bath treatment for amoebic gill disease caused by Neoparamoeba spp. Vet Parasitol. 2007 Mar 31;144(3-4):197-207. PubMed PMID: 17129675.
7: Matsubara K, Sanoh S, Ohta S, Kitamura S, Sugihara K, Fujimoto N. An improved thyroid hormone reporter assay to determine the thyroid hormone-like activity of amiodarone, bithionol, closantel and rafoxanide. Toxicol Lett. 2012 Jan 5;208(1):30-5. doi: 10.1016/j.toxlet.2011.10.004. PubMed PMID: 22015988.
8: Sakamoto M, Takeba K, Sasamoto T, Kusano T, Hayashi H, Kanai S, Kanda M, Nagayama T. Determination of bithionol, bromophen, nitroxynil, oxyclozanide, and tribromsalan in milk with liquid chromatography coupled with tandem mass spectrometry. J AOAC Int. 2010 Jul-Aug;93(4):1340-6. PubMed PMID: 20922970.
9: Kleinboelting S, Ramos-Espiritu L, Buck H, Colis L, van den Heuvel J, Glickman JF, Levin LR, Buck J, Steegborn C. Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site. J Biol Chem. 2016 Apr 29;291(18):9776-84. doi: 10.1074/jbc.M115.708255. PubMed PMID: 26961873; PubMed Central PMCID: PMC4850313.
10: Reid L, Clothier RH, Khammo N. Hydrogen peroxide induced stress in human keratinocytes and its effect on bithionol toxicity. Toxicol In Vitro. 2001 Aug-Oct;15(4-5):441-5. PubMed PMID: 11566576.
11: Leonardi W, Zilbermintz L, Cheng LW, Zozaya J, Tran SH, Elliott JH, Polukhina K, Manasherob R, Li A, Chi X, Gharaibeh D, Kenny T, Zamani R, Soloveva V, Haddow AD, Nasar F, Bavari S, Bassik MC, Cohen SN, Levitin A, Martchenko M. Bithionol blocks pathogenicity of bacterial toxins, ricin, and Zika virus. Sci Rep. 2016 Sep 30;6:34475. doi: 10.1038/srep34475. PubMed PMID: 27686742; PubMed Central PMCID: PMC5043268.
12: Ayyagari VN, Johnston NA, Brard L. Assessment of the antitumor potential of Bithionol in vivo using a xenograft model of ovarian cancer. Anticancer Drugs. 2016 Jul;27(6):547-59. doi: 10.1097/CAD.0000000000000364. PubMed PMID: 27058706; PubMed Central PMCID: PMC5053334.
13: Eleuteri S, Di Giovanni S, Rockenstein E, Mante M, Adame A, Trejo M, Wrasidlo W, Wu F, Fraering PC, Masliah E, Lashuel HA. Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease. Neurobiol Dis. 2015 Feb;74:144-57. doi: 10.1016/j.nbd.2014.08.017. PubMed PMID: 25173807; PubMed Central PMCID: PMC4323687.
14: Kodama K. [Human fascioliasis: comparison of a fasciolicidal effect of bithionol and praziquantel]. Kansenshogaku Zasshi. 1997 Nov;71(11):1162-7. Review. Japanese. PubMed PMID: 9455057.
15: Hozumi H, Hokari R, Kurihara C, Narimatsu K, Sato H, Sato S, Ueda T, Higashiyama M, Okada Y, Watanabe C, Komoto S, Tomita K, Kawaguchi A, Nagao S, Miura S. Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration. Lab Invest. 2013 May;93(5):508-19. doi: 10.1038/labinvest.2013.45. PubMed PMID: 23478591.
| Chemical | |
|---|---|
| CAS Num | 97-18-7 |
| Chemical Formula | C12H6Cl4O2S |
| Molecular Weight | 356.038 |
| IUPAC Chemical Name | 6,6'-thiobis(2,4-dichlorophenol) |
| Exact Mass | 353.8843 |
| Elemental Analysis | C, 40.48; H, 1.70; Cl, 39.83; O, 8.99; S, 9.00 |
| Synonym | Bithionol; Bitin; CP 3438; CP-3438; CP3438; Lorothidol; NSC 47129; NSC-47129; NSC47129 |
| Solubility | Soluble in DMSO |
| SMILES Code | ClC1=CC(Cl)=C(O)C(SC2=CC(Cl)=CC(Cl)=C2O)=C1 |
| Biological | |
| Targets and Effects | N/A |
| Pathways | Apoptosis |
| Physical | |
| Appearance | Solid powder |
| Purity | >98% (or refer to the Certificate of Analysis) |
| Shipping Condition | Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. |
| Storage Condition | Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
| Shelf Life | >2 years if stored properly |
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