MedKoo product information:

Carbendazim

Carbendazim is a widely used broad-spectrum benzimidazole fungicide. A 4.7% solution of carbendazim hydrochloride is sold as Eertavas, an effective treatment for Dutch elm disease. Carbendazim was included in a biocide ban proposed by the Swedish Chemicals Agency  and approved by the European Parliament in January 13, 2009. The fungicide is controversially used in Queensland, Australia on macadamia plantations.

Carbendazim is also an anticancer drug candidate, currently being investigated by AmpliMed.  It also inhibits proliferation of human cancer cells, including drug- and multidrug-resistant and p53-deficient cell lines. Because of its promising preclinical anti-tumor activity, it has undergone phase I clinical trials and is under further clinical development.  Carbendazim inhibits proliferation (IC50, 10 μM) of MCF7 human breast cancer cells and half-maximally arrests mitosis at a similar concentration (8 μM), in concert with suppression of microtubule dynamic instability without appreciable microtubule depolymerization. It induces mitotic spindle abnormalities and reduces the metaphase intercentromere distance of sister chromatids, indicating reduction of tension on kinetochores, thus leading to metaphase arrest. With microtubules assembled in vitro from pure tubulin, carbendazim also suppresses dynamic instability, reducing the dynamicity by 50% at 10 μM, with only minimal (21%) reduction of polymer mass. Carbendazim binds to mammalian tubulin (Kd, 42.8 ± 4.0 μM). Unlike some benzimidazoles that bind to the colchicine site in tubulin, carbendazim neither competes with colchicine nor competes with vinblastine for binding to brain tubulin. Thus, carbendazim binds to an as yet unidentified site in tubulin and inhibits tumor cell proliferation by suppressing the growing and shortening phases of microtubule dynamic instability, thus inducing mitotic arrest. (source: Yenjerla M, Cox C, Wilson L, Jordan MA. Carbendazim inhibits cancer cell proliferation by suppressing microtubule dynamics. J Pharmacol Exp Ther. 2009 Feb;328(2):390-8. Epub 2008 Nov 10.

Current developer:    AmpliMed.

1: Clément MJ, Rathinasamy K, Adjadj E, Toma F, Curmi PA, Panda D. Benomyl and colchicine synergistically inhibit cell proliferation and mitosis: evidence of distinct binding sites for these agents in tubulin. Biochemistry. 2008 Dec 9;47(49):13016-25. PubMed PMID: 19049291.

2: Yenjerla M, Cox C, Wilson L, Jordan MA. Carbendazim inhibits cancer cell proliferation by suppressing microtubule dynamics. J Pharmacol Exp Ther. 2009 Feb;328(2):390-8. Epub 2008 Nov 10. PubMed PMID: 19001156; PubMed Central PMCID:  PMC2682274.

3: Fellows MD, O'Donovan MR. Cytotoxicity in cultured mammalian cells is a function of the method used to estimate it. Mutagenesis. 2007 Jul;22(4):275-80. Epub 2007 Apr 24. PubMed PMID: 17456508.

4: Carazo-Salas RE, Antony C, Nurse P. The kinesin Klp2 mediates polarization of  interphase microtubules in fission yeast. Science. 2005 Jul 8;309(5732):297-300. PubMed PMID: 16002618.

5: Pardo M, Nurse P. Equatorial retention of the contractile actin ring by microtubules during cytokinesis. Science. 2003 Jun 6;300(5625):1569-74. PubMed PMID: 12791993.

6: McCarroll NE, Protzel A, Ioannou Y, Frank Stack HF, Jackson MA, Waters MD, Dearfield KL. A survey of EPA/OPP and open literature on selected pesticide chemicals. III. Mutagenicity and carcinogenicity of benomyl and carbendazim. Mutat Res. 2002 Sep;512(1):1-35. Review. PubMed PMID: 12220588

7: Hao D, Rizzo JD, Stringer S, Moore RV, Marty J, Dexter DL, Mangold GL, Camden  JB, Von Hoff DD, Weitman SD. Preclinical antitumor activity and pharmacokinetics of methyl-2-benzimidazolecarbamate (FB642). Invest New Drugs. 2002 Aug;20(3):261-70. PubMed PMID: 12201489.

8: Hammond LA, Davidson K, Lawrence R, Camden JB, Von Hoff DD, Weitman S, Izbicka E. Exploring the mechanisms of action of FB642 at the cellular level. J Cancer Res Clin Oncol. 2001 May;127(5):301-13. PubMed PMID: 11355145.

9: Crane R, Craig R, Murray R, Dunand-Sauthier I, Humphrey T, Norbury C. A fission yeast homolog of Int-6, the mammalian oncoprotein and eIF3 subunit, induces drug resistance when overexpressed. Mol Biol Cell. 2000 Nov;11(11):3993-4003. PubMed PMID: 11071922; PubMed Central PMCID: PMC15052.

10: Brunner D, Nurse P. CLIP170-like tip1p spatially organizes microtubular dynamics in fission yeast. Cell. 2000 Sep 1;102(5):695-704. PubMed PMID: 11007487.

11: Backlund M, Weidolf L, Ingelman-Sundberg M. Structural and mechanistic aspects of transcriptional induction of cytochrome P450 1A1 by benzimidazole derivatives in rat hepatoma H4IIE cells. Eur J Biochem. 1999 Apr;261(1):66-71. PubMed PMID: 10103034.

12: Szankasi P, Smith GR. Requirement of S. pombe exonuclease II, a homologue of  S. cerevisiae Sep1, for normal mitotic growth and viability. Curr Genet. 1996 Sep;30(4):284-93. PubMed PMID: 8781170.

13: Börzsönyi M, Pintér A, Surján A, Farkas I. Transplacental induction of lymphomas in Swiss mice by carbendazim and sodium nitrite. Int J Cancer. 1976 Jun 15;17(6):742-7. PubMed PMID: 988851.

14: Börzsönyi M, Csik M. Induction of malignant lymphomas in swiss mice by n-nitroso compounds formed in vivo. Int J Cancer. 1975 May 15;15(5):830-8. PubMed PMID: 1140875.