Combretastatin A-4 Derived Imidazoles Show Cytotoxic, Antivascular, and Antimetastatic Effects Based on Cytoskeletal Reorganisation

Overview

Journal Invest New Drugs

Publisher Springer

Specialty Oncology

Date 2015 Feb 14

PMID 25678082

Citations 9

Authors

Katharina Mahal

Bernhard Biersack

Henrike Caysa

Rainer Schobert

Thomas Mueller

Affiliations

Soon will be listed here.

Abstract

Introduction: Combretastatin A-4 (CA-4) is a natural cis-stilbene which interferes with the cellular tubulin dynamics and which selectively destroys tumour blood vessels. Its pharmacological shortcomings such as insufficient chemical stability, water solubility, and cytotoxicity can be remedied by employing its imidazole derivatives.

Methods: We studied 11 halogenated imidazole derivatives of CA-4 for their effects on the microtubule and actin cytoskeletons of cancer and endothelial cells and on the propensity of these cells to migrate across tissue barriers or to form blood vessel-like tubular structures.

Results: A series of N-methyl-4-aryl-5-(4-ethoxyphenyl)-imidazoles proved far more efficacious than the lead CA-4 in growth inhibition assays against CA-4-resistant HT-29 colon carcinoma cells and generally more selective for cancer over nonmalignant cells. Et-brimamin (6), the most active compound, inhibited the growth of various cancer cell lines with IC50 (72 h) values in the low nanomolar range. Active imidazoles such as 6 reduced the motility and invasiveness of cancer cells by initiating the formation of actin stress fibres and focal adhesions as a response to the extensive microtubule disruption. The antimetastatic properties were ascertained in 3D-transwell migration assays which simulated the transgression of highly invasive melanoma cells through the extracellular matrix of solid tumours and through the endothelium of blood vessels. The studied imidazoles exhibited vascular-disrupting effects also against tumour xenografts that are refractory to CA-4. They were also less toxic and better tolerated by mice.

Conclusions: We deem the new imidazoles promising drug candidates for combination regimens with antiangiogenic VEGFR inhibitors.

Citing Articles

Natural Products as Regulators against Matrix Metalloproteinases for the Treatment of Cancer.

Islam M, Jang N, Lee H Biomedicines. 2024; 12(4).

PMID: 38672151 PMC: 11048580. DOI: 10.3390/biomedicines12040794.

Imidazole Analogs of Vascular-Disrupting Combretastatin A-4 with Pleiotropic Efficacy against Resistant Colorectal Cancer Models.

Reipsch F, Biersack B, Lucas H, Schobert R, Mueller T Int J Mol Sci. 2021; 22(23).

PMID: 34884888 PMC: 8658273. DOI: 10.3390/ijms222313082.

Development Of Novel Liposome-Encapsulated Combretastatin A4 Acylated Derivatives: Prodrug Approach For Improving Antitumor Efficacy.

Gu Y, Ma J, Fu Z, Xu Y, Gao B, Yao J Int J Nanomedicine. 2019; 14:8805-8818.

PMID: 31806973 PMC: 6844228. DOI: 10.2147/IJN.S210938.

Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer.

Steinemann G, Dittmer A, Schmidt J, Josuttis D, Fahling M, Biersack B Mol Oncol. 2019; 13(12):2679-2696.

PMID: 31583820 PMC: 6887589. DOI: 10.1002/1878-0261.12582.

Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure⁻Activity Relations of New Inhibitors of HDAC and/or Tubulin Function.

Schmitt F, Gosch L, Dittmer A, Rothemund M, Mueller T, Schobert R Int J Mol Sci. 2019; 20(2).

PMID: 30658435 PMC: 6359144. DOI: 10.3390/ijms20020383.

References

Salmon H, Siemann D . Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity. Clin Cancer Res. 2006; 12(13):4090-4. DOI: 10.1158/1078-0432.CCR-06-0163. View

Kanthou C, Tozer G . The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells. Blood. 2002; 99(6):2060-9. DOI: 10.1182/blood.v99.6.2060. View

Werr J, Xie X, Hedqvist P, Ruoslahti E, Lindbom L . beta1 integrins are critically involved in neutrophil locomotion in extravascular tissue In vivo. J Exp Med. 1998; 187(12):2091-6. PMC: 2212368. DOI: 10.1084/jem.187.12.2091. View

Chang C, Yu F, Wu T, Wang L, Liu B . Mycotoxin citrinin induced cell cycle G2/M arrest and numerical chromosomal aberration associated with disruption of microtubule formation in human cells. Toxicol Sci. 2010; 119(1):84-92. DOI: 10.1093/toxsci/kfq309. View

Ebos J, Lee C, Cruz-Munoz W, Bjarnason G, Christensen J, Kerbel R . Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009; 15(3):232-9. PMC: 4540346. DOI: 10.1016/j.ccr.2009.01.021. View

Lamalice L, Le Boeuf F, Huot J . Endothelial cell migration during angiogenesis. Circ Res. 2007; 100(6):782-94. DOI: 10.1161/01.RES.0000259593.07661.1e. View

Lunt S, Akerman S, Hill S, Fisher M, Wright V, Reyes-Aldasoro C . Vascular effects dominate solid tumor response to treatment with combretastatin A-4-phosphate. Int J Cancer. 2010; 129(8):1979-89. DOI: 10.1002/ijc.25848. View

Orgaz J, Sanz-Moreno V . Emerging molecular targets in melanoma invasion and metastasis. Pigment Cell Melanoma Res. 2012; 26(1):39-57. DOI: 10.1111/pcmr.12041. View

Quan H, Xu Y, Lou L . p38 MAPK, but not ERK1/2, is critically involved in the cytotoxicity of the novel vascular disrupting agent combretastatin A4. Int J Cancer. 2007; 122(8):1730-7. DOI: 10.1002/ijc.23262. View

10.

van Nieuw Amerongen G, van Hinsbergh V . Cytoskeletal effects of rho-like small guanine nucleotide-binding proteins in the vascular system. Arterioscler Thromb Vasc Biol. 2001; 21(3):300-11. DOI: 10.1161/01.atv.21.3.300. View

11.

Bhalla K . Microtubule-targeted anticancer agents and apoptosis. Oncogene. 2003; 22(56):9075-86. DOI: 10.1038/sj.onc.1207233. View

12.

Biersack B, Muthukumar Y, Schobert R, Sasse F . Cytotoxic and antivascular 1-methyl-4-(3-fluoro-4-methoxyphenyl)-5-(halophenyl)-imidazoles. Bioorg Med Chem Lett. 2011; 21(21):6270-3. DOI: 10.1016/j.bmcl.2011.09.005. View

13.

Nitzsche B, Gloesenkamp C, Schrader M, Ocker M, Preissner R, Lein M . Novel compounds with antiangiogenic and antiproliferative potency for growth control of testicular germ cell tumours. Br J Cancer. 2010; 103(1):18-28. PMC: 2905278. DOI: 10.1038/sj.bjc.6605725. View

14.

Schwartz E . Antivascular actions of microtubule-binding drugs. Clin Cancer Res. 2009; 15(8):2594-601. PMC: 2745203. DOI: 10.1158/1078-0432.CCR-08-2710. View

15.

Friedl P, Wolf K . Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003; 3(5):362-74. DOI: 10.1038/nrc1075. View

16.

Hofmann U, Houben R, Brocker E, Becker J . Role of matrix metalloproteinases in melanoma cell invasion. Biochimie. 2005; 87(3-4):307-14. DOI: 10.1016/j.biochi.2005.01.013. View

17.

Mikaelian I, Buness A, de Vera-Mudry M, Kanwal C, Coluccio D, Rasmussen E . Primary endothelial damage is the mechanism of cardiotoxicity of tubulin-binding drugs. Toxicol Sci. 2010; 117(1):144-51. DOI: 10.1093/toxsci/kfq189. View

18.

Laferriere J, Houle F, Taher M, Valerie K, Huot J . Transendothelial migration of colon carcinoma cells requires expression of E-selectin by endothelial cells and activation of stress-activated protein kinase-2 (SAPK2/p38) in the tumor cells. J Biol Chem. 2001; 276(36):33762-72. DOI: 10.1074/jbc.M008564200. View

19.

Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F . Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009; 15(3):220-31. PMC: 2874829. DOI: 10.1016/j.ccr.2009.01.027. View

20.

Kanthou C, Greco O, Stratford A, Cook I, Knight R, Benzakour O . The tubulin-binding agent combretastatin A-4-phosphate arrests endothelial cells in mitosis and induces mitotic cell death. Am J Pathol. 2004; 165(4):1401-11. PMC: 3118836. DOI: 10.1016/S0002-9440(10)63398-6. View