Faculty

Francis Swaby Markland, PhD
Francis Swaby Markland, PhD
Professor of Biochemistry & Molecular Medicine
Medicine
HMR 813A, 2011 Zonal Ave. Off Campus Los Angeles
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.

UCLA: NIH Career Development Award, 1968-1973

Methods for Evaluation of a Snake Venom-Derived Disintegrin in Animal Models of Human Cancer Methods Mol Biol. 2020; 2068:185-204. . View in PubMed

Preclinical evaluation of a 64Cu-labeled disintegrin for PET imaging of prostate cancer Amino Acids. 2019 Oct 16. . View in PubMed

A Novel Venom-Derived Peptide for Brachytherapy of Glioblastoma: Preclinical Studies in Mice Molecules. 2018 Nov 08; 23(11). . View in PubMed

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 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 04; 2(4):793-808. . 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 17 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

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

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

Alpha-fibrinogenases Curr Drug Targets Cardiovasc Haematol Disord. 2004 Dec; 4(4):417-35. . 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

Effect of BJcuL (a lectin from the venom of the snake Bothrops jararacussu) on adhesion and growth of tumor and endothelial cells Toxicon. 2001 Oct; 39(10):1471-6. . 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

Differential regulation of tyrosine phosphorylation in tumor cells by contortrostatin, a homodimeric disintegrin, and monomeric disintegrins echistatin and flavoridin Toxicon. 2001 Feb-Mar; 39(2-3):283-9. . View in PubMed

Three-dimensional structure of fibrolase, the fibrinolytic enzyme from southern copperhead venom, modeled from the X-ray structure of adamalysin II and atrolysin C AAPS PharmSci. 2001; 3(2):E16. . View in PubMed

Contortrostatin, a homodimeric disintegrin, actively disrupts focal adhesion and cytoskeletal structure and inhibits cell motility through a novel mechanism Cell Commun Adhes. 2001; 8(2):71-86. . View in PubMed

Chimeric derivative of fibrolase, a fibrinolytic enzyme from southern copperhead venom, possesses inhibitory activity on platelet aggregation Arch Biochem Biophys. 2000 Dec 15; 384(2):227-37. . View in PubMed

Anti-invasive effect of contortrostatin, a snake venom disintegrin, and TNF-alpha on malignant glioma cells Anticancer Res. 2000 Nov-Dec; 20(6B):4227-33. . View in PubMed

Action of metalloproteinases mutalysin I and II on several components of the hemostatic and fibrinolytic systems Thromb Res. 2000 Aug 15; 99(4):363-76. . View in PubMed

Contortrostatin activates ERK2 and tyrosine phosphorylation events via distinct pathways Biochem Biophys Res Commun. 2000 Jul 21; 274(1):142-8. . View in PubMed

Contortrostatin, a snake venom disintegrin, induces alphavbeta3-mediated tyrosine phosphorylation of CAS and FAK in tumor cells J Cell Biochem. 2000 Jul 19; 79(1):28-37. . View in PubMed

Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix contortrix, inhibits breast cancer progression Breast Cancer Res Treat. 2000 Jun; 61(3):249-60. . View in PubMed

Molecular cloning and functional expression of contortrostatin, a homodimeric disintegrin from southern copperhead snake venom Arch Biochem Biophys. 2000 Mar 15; 375(2):278-88. . View in PubMed

Contortrostatin, a homodimeric disintegrin, binds to integrin alphavbeta5 Biochem Biophys Res Commun. 2000 Jan 07; 267(1):350-5. . View in PubMed

Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix contortrix, inhibits angiogenesis Angiogenesis. 1999; 3(3):259-69. . View in PubMed

Snake venoms and the hemostatic system Toxicon. 1998 Dec; 36(12):1749-800. . View in PubMed

Snake venom fibrinogenolytic and fibrinolytic enzymes: an updated inventoryRegistry of Exogenous Hemostatic Factors of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1998 Mar; 79(3):668-74. . View in PubMed

Contortrostatin, a homodimeric snake venom disintegrin, is a potent inhibitor of osteoclast attachment J Bone Miner Res. 1998 Mar; 13(3):409-14. . View in PubMed

Proteolytic cleavage of the beta1 subunit of platelet alpha2beta1 integrin by the metalloproteinase jararhagin compromises collagen-stimulated phosphorylation of pp72 J Biol Chem. 1997 Dec 19; 272(51):32599-605. . View in PubMed

Chimeric fibrolase: covalent attachment of an RGD-like peptide to create a potentially more effective thrombolytic agent Thromb Res. 1997 Aug 01; 87(3):289-302. . View in PubMed

Snake venoms Drugs. 1997; 54 Suppl 3:1-10. . View in PubMed

Fibrolase, an active thrombolytic enzyme in arterial and venous thrombosis model systems Adv Exp Med Biol. 1996; 391:427-38. . View in PubMed

Resolution of isoforms of natural and recombinant fibrolase, the fibrinolytic enzyme from Agkistrodon contortrix contortrix snake venom, and comparison of their EDTA sensitivities J Chromatogr B Biomed Appl. 1994 Dec 09; 662(2):227-43. . View in PubMed

Purification and characterization of fibrolase isoforms from venom of individual southern copperhead (Agkistrodon contortrix Contortrix) snakes Toxicon. 1994 Dec; 32(12):1521-31. . View in PubMed

Thrombolytic effects of recombinant fibrolase or APSAC in a canine model of carotid artery thrombosis Circulation. 1994 Nov; 90(5):2448-56. . View in PubMed

Contortrostatin, a snake venom disintegrin, inhibits beta 1 integrin-mediated human metastatic melanoma cell adhesion and blocks experimental metastasis Cancer Res. 1994 Sep 15; 54(18):4993-8. . View in PubMed

Structurally distinct disintegrins contortrostatin and multisquamatin differentially regulate platelet tyrosine phosphorylation J Biol Chem. 1994 Sep 02; 269(35):21940-3. . View in PubMed

Fibrinolytic enzymes from the venoms of Agkistrodon contortrix contortrix and Crotalus basiliscus basiliscus: cleavage site specificity towards the alpha-chain of fibrin Thromb Res. 1994 May 15; 74(4):355-67. . View in PubMed

Purification and characterization of platelet aggregation inhibitors from snake venoms Thromb Res. 1994 Jan 01; 73(1):39-52. . View in PubMed

Purification, characterization, and fibrinogen cleavage sites of three fibrinolytic enzymes from the venom of Crotalus basiliscus basiliscus Biochemistry. 1992 May 19; 31(19):4547-57. . View in PubMed

Amino acid sequence of fibrolase, a direct-acting fibrinolytic enzyme from Agkistrodon contortrix contortrix venom Protein Sci. 1992 May; 1(5):590-600. . View in PubMed

A hemorrhagic (basement membrane degrading) zinc metalloproteinase from southern copperhead venom Matrix Suppl. 1992; 1:101-3. . View in PubMed

Purification and characterization of a fibrinolytic enzyme from venom of the southern copperhead snake (Agkistrodon contortrix contortrix) Arch Biochem Biophys. 1991 Sep; 289(2):197-207. . View in PubMed

Inventory of alpha- and beta-fibrinogenases from snake venomsFor the Subcommittee on Nomenclature of Exogenous Hemostatic Factors of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1991 Apr 08; 65(4):438-43. . View in PubMed

Immunological properties of the fibrinolytic enzyme (fibrolase) from southern copperhead (Agkistrodon contortrix contortrix) venom and its purification by immunoaffinity chromatography Toxicon. 1991; 29(6):683-94. . View in PubMed

HPLC-based two-step purification of fibrinolytic enzymes from the venom of Agkistrodon contortrix contortrix and Agkistrodon piscivorus conanti Protein Expr Purif. 1990 Sep; 1(1):33-9. . View in PubMed

Biochemical characteristics of fibrolase, a fibrinolytic protease from snake venom Haemostasis. 1990; 20(3):147-54. . View in PubMed

Glucocorticoid receptor from lactating goat mammary tissue comparison of native and activated forms in a cell free system J Steroid Biochem. 1989 May; 32(5):651-68. . View in PubMed

A direct-acting fibrinolytic enzyme from the venom of Agkistrodon contortrix contortrix: effects on various components of the human blood coagulation and fibrinolysis systems Thromb Res. 1988 Dec 15; 52(6):541-52. . View in PubMed

Isoelectric focusing in immobilized pH gradients of a snake venom fibrinolytic enzyme J Biochem Biophys Methods. 1988 Jun-Jul; 16(2-3):215-26. . View in PubMed

Isolation by preparative isoelectric focusing of a direct acting fibrinolytic enzyme from the venom of Agkistrodon contortrix contortrix (southern copperhead) Toxicon. 1987; 25(11):1189-98. . View in PubMed

Antitumor action of crotalase, a defibrinogenating snake venom enzyme Semin Thromb Hemost. 1986 Oct; 12(4):284-90. . View in PubMed

Comparison of two methods for proteolytic enzyme detection in snake venom Toxicon. 1986; 24(4):385-93. . View in PubMed

Preparation of a new antivenin by affinity chromatography Am J Trop Med Hyg. 1985 Jan; 34(1):141-50. . View in PubMed

RNA induced reversal of glucocorticoid receptor activation Biochem Biophys Res Commun. 1982 Mar 15; 105(1):20-7. . View in PubMed

Kallikrein-like activity of crotalase, a snake venom enzyme that clots fibrinogen Proc Natl Acad Sci U S A. 1982 Mar; 79(6):1688-92. . View in PubMed

Effect of molybdate on androgen receptor levels in canine prostate Prostate. 1982; 3(6):611-4. . View in PubMed

Thrombin-like and fibrinolytic enzymes in the venoms from the Gaboon viper (Bitis gabonica), eastern cottonmouth moccasin (Agkistrodon ppiscivorus) and southern copperhead (Agkistrodon c. contortrix) snakes. Toxicon. 1982; 20(2):427-32. . View in PubMed

Thrombolytic agents in snake venoms Proc West Pharmacol Soc. 1982; 25:353-6. . View in PubMed

Physicochemical analysis of reversible molybdate effects on different molecular forms of glucocorticoid receptor Biochem Biophys Res Commun. 1981 Nov 16; 103(1):60-7. . View in PubMed

The inhibition of crotalase, a thrombin-like snake venom enzyme, by several peptide chloromethyl ketone derivatives Biochem Biophys Res Commun. 1981 Oct 30; 102(4):1302-9. . View in PubMed

The primary structure of crotalase, a thrombin-like venom enzyme, exhibits closer homology to kallikrein than to other serine proteases Biochem Biophys Res Commun. 1981 Mar 31; 99(2):715-21. . View in PubMed

Fibrinolytic and fibrinogen clotting enzymes present in the venoms of western diamondback rattlesnake, Crotalus atrox, eastern diamondback rattlesnake, Crotalus adamanteus, and southern Pacific rattlesnake, Crotalus viridis helleri Toxicon. 1981; 19(1):53-9. . View in PubMed

Fibrinolytic enzyme(s) in western diamondback rattlesnake (Crotalus atrox) venom Toxicon. 1980; 18(3):285-90. . View in PubMed

A new method for purification of the thrombin-like enzyme from the venom of the eastern diamondback rattlesnake Thromb Res. 1979; 16(1-2):11-23. . View in PubMed

Thrombin-like enzyme from the venom of Crotalus adamanteus (eastern diamondback rattlesnake) Thromb Res. 1977 Mar; 10(3):487-94. . View in PubMed

Modification of yeast 3-phosphoglycerate kinase: isolation and sequence determination of a nitrated active-site peptide and isolation of a carboxyl modified active-site peptide Biochem Biophys Res Commun. 1977 Jan 10; 74(1):165-71. . View in PubMed

Characterization of a thrombin-like enzyme from Crotalus adamanteus (Eastern diamondback rattlesnake) [proceedings] Toxicon. 1976; 14(6):412-3. . View in PubMed

A purified procoagulant enzyme from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus): in vivo and in vitro studies J Lab Clin Med. 1972 Jun; 79(6):906-23. . View in PubMed

Purification and properties of a thrombin-like enzyme from the venom of Crotalus adamanteus (Eastern diamondback rattlesnake) J Biol Chem. 1971 Nov; 246(21):6460-73. . View in PubMed

Powered by SC CTSI