Faculty

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Francis Swaby Markland, PhD
Professor of Biochemistry & Molecular Medicine
Medicine
HMR 813, 2011 Zonal Ave. Off Campus Los Angeles
+1 323 442 2747

Overview

DISINTEGRINS - EFFECTIVE INHIBITORS OF CANCER INVASION AND DISSEMINATION:
We have been studying a peptide from southern copperhead snake venom that we call contortrostatin (CN). CN is a homodimer with two identical chains held together by two inter-chain disulfide bonds. The peptide possesses potent anti-tumor and anti-invasive activity. CN is a member of a family of peptides called disintegrins that are found in snake venoms. Many members of this family are distinguished by the presence of an amino acid sequence, arginine-glycine-aspartic acid (RGD), that enables them to bind to a subset of cell surface receptors called integrins found on cancer cells and newly growing (angiogenic) blood vessels supplying the tumor. Integrins mediate interactions between cells and their surroundings, and on cancer cells they play important roles in tumor invasion and dissemination. We postulated that since contortrostatin disrupts integrin interactions, it should block both cancer cell and newly growing blood vessel cell integrins and may, therefore, have significant anti-angiogenic and anti-metastatic activity. We have shown that CN acts as an effective inhibitor of breast cancer progression. Importantly, CN displays impressive inhibitory activity on the growth of new blood vessels into the breast cancer. But, there is a problem with CN and that is it is present in snake venom in very small quantities, making its translation to the clinic very difficult. However, we recently succeeded in producing a recombinant version of CN using an E. coli expression system. The recombinant protein is a monomer, called vicrostatin (VCN), purposefully designed with a slightly different amino acid sequence at its COOH-terminus to improve binding affinity to an important member of the integrin family. Using a delivery system in which VCN is encapsulated in unilamellar lipid particles (liposomes), we have shown that intravenous delivery of the liposomal formulation (LVCN) twice weekly in animal models of human, triple-negative, metastatic breast cancer, or human prostate cancer, leads to close to 80% inhibition of tumor growth and angiogenesis. More recently we have been examining the effect of VCN introduced intraperitoneally on the growth of human ovarian cancer cells in mice and have observed potent inhibition of tumor growth and dissemination. Presently we are studying human breast, prostate and ovarian cancer and glioma (a devastating brain tumor) animal models to demonstrate the anti-invasive and anti-tumor activities of VCN. We are also examining the mechanism by which VCN dramatically disrupts the actin cytoskeleton of cancer and angiogenic blood vessel cells leading to an abrupt halt to the locomotor apparatus of these cells. Finally, we are examining the diagnostic activity of VCN as an imaging agent to detect integrin positive cancer in prostate cancer mouse model studies, and then use VCN to treat the tumor.
In separate studies we are examining another class of related proteins derived from members of the ADAM (A Disintegrin and Metalloproteinase domain) family. We are able to recombinantly produce large quantities of the disintegrin domain (DD) of the ADAM proteins using a highly engineered bacterial expression system. One of these ADAM DDs has interesting antitumor activity based on its interaction with integrins on the tumor cell surface. Since members of the ADAM family have different structures of their DDs, we are interested in characterizing the integrin binding specificities and affinities of these ADAM DDs and characterizing their biological activities with potential application to human cancer or other diseases.

Awards

UCLA: NIH Career Development Award, 1968-1973

Publications

Multimeric disintegrin protein polymer fusions that target tumor vasculature. Biomacromolecules. 2014 Jul 14; 15(7):2347-58. View in: PubMed

Reversal of thienopyridine-induced platelet dysfunction following desmopressin administration. J Med Toxicol. 2013 Jun; 9(2):139-43. View in: PubMed

Snake venom metalloproteinases. Toxicon. 2013 Feb; 62:3-18. View in: PubMed

Hirudin and s18886 maintain luminal patency after thrombolysis with alfimeprase. J Cardiovasc Pharmacol. 2013 Feb; 61(2):152-9. View in: PubMed

Development of a chimeric recombinant disintegrin as a cost-effective anti-cancer agent with promising translational potential. Toxicon. 2012 Mar 15; 59(4):472-86. View in: PubMed

Contortrostatin, a homodimeric disintegrin isolated from snake venom inhibits herpes simplex virus entry and cell fusion. Antivir Ther. 2012; 17(7):1319-26. View in: PubMed

The disintegrin contortrostatin in combination with docetaxel is a potent inhibitor of prostate cancer in vitro and in vivo. Prostate. 2010 Sep 1; 70(12):1359-70. View in: PubMed

The disintegrin contortrostatin in combination with docetaxel is a potent inhibitor of prostate cancer in vitro and in vivo. Prostate. 2010 Sep 01; 70(12):1359-70. View in: PubMed

Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities. PLoS One. 2010 Jun 03; 5(6):e10929. View in: PubMed

Fibrolase: trials and tribulations. Toxins (Basel). 2010 Apr; 2(4):793-808. View in: PubMed

Fibrolase: trials and tribulations. Toxins (Basel). 2010 04; 2(4):793-808. View in: PubMed

Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities. PLoS One. 2010; 5(6):e10929. View in: PubMed

The use of pepsin in receptor internalization assays. Biochem Biophys Res Commun. 2009 Oct 16; 388(2):240-6. View in: PubMed

Structure of acostatin, a dimeric disintegrin from Southern copperhead (Agkistrodon contortrix contortrix), at 1. 7 A resolution. Acta Crystallogr D Biol Crystallogr. 2008 Apr; 64(Pt 4):466-70. View in: PubMed

Anti-angiogenesis and RGD-containing snake venom disintegrins. Curr Pharm Des. 2007; 13(28):2860-71. View in: PubMed

The role of contortrostatin, a snake venom disintegrin, in the inhibition of tumor progression and prolongation of survival in a rodent glioma model. J Neurosurg. 2005 Sep; 103(3):526-37. View in: PubMed

Potent mimicry of fibronectin-induced intracellular signaling in glioma cells by the homodimeric snake venom disintegrin contortrostatin. Neurosurgery. 2005 Jul; 57(1):141-53; discussion 141-53. View in: PubMed

Snake venom fibrin(ogen)olytic enzymes. Toxicon. 2005 Jun 15; 45(8):1021-39. View in: PubMed

Development of a novel recombinant disintegrin, contortrostatin, as an effective anti-tumor and anti-angiogenic agent. Pathophysiol Haemost Thromb. 2005; 34(4-5):177-83. View in: PubMed

Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells. Anticancer Res. 2005 Jan-Feb; 25(1A):249-53. View in: PubMed

Contortrostatin, a snake venom disintegrin with anti-angiogenic and anti-tumor activity. Pathophysiol Haemost Thromb. 2005; 34(4-5):169-76. View in: PubMed

Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression. Mol Cancer Ther. 2004 Apr; 3(4):499-511. View in: PubMed

Anti-angiogenic activity of contortrostatin, a disintegrin from Agkistrodon contortrix contortrix snake venom. Angiogenesis. 2003; 6(3):213-24. View in: PubMed

Functional effect of contortrostatin, a snake venom disintegrin, on human glioma cell invasion in vitro. Cell Commun Adhes. 2003 Jan-Feb; 10(1):1-16. View in: PubMed

Purification, crystallization and preliminary X-ray analysis of the disintegrin contortrostatin from Agkistrodon contortrix contortrix snake venom. Acta Crystallogr D Biol Crystallogr. 2002 Dec; 58(Pt 12):2122-4. View in: PubMed

A novel snake venom disintegrin that inhibits human ovarian cancer dissemination and angiogenesis in an orthotopic nude mouse model. Haemostasis. 2001 May-Dec; 31(3-6):183-91. View in: PubMed

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