New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

被引:11
作者
Barash, Uri [1 ]
Rangappa, Shobith [2 ]
Mohan, Chakrabhavi Dhananjaya [3 ]
Vishwanath, Divakar [4 ]
Boyango, Ilanit [1 ]
Basappa, Basappa [4 ]
Vlodavsky, Israel [1 ]
Rangappa, Kanchugarakoppal S. [5 ]
机构
[1] Technion, Technion Integrated Canc Ctr TICC, Rappaport Fac Med, IL-31096 Haifa, Israel
[2] Adichunchanagiri Inst Mol Med, Bg Nagara 571448, Nagamangala Tal, India
[3] Univ Mysore, Dept Studies Mol Biol, Mysore 570006, Karnataka, India
[4] Univ Mysore, Dept Studies Organ Chem, Lab Chem Biol, Mysore 570006, Karnataka, India
[5] Univ Mysore, Inst Excellence, Vijnana Bhavan, Mysore 570006, Karnataka, India
基金
以色列科学基金会;
关键词
triazolo-thiadiazoles; small molecules; heparanase-inhibiting compounds; primary tumor growth; cell invasion; metastasis; EXTRACELLULAR-MATRIX; TARGET; PROTEOGLYCAN; SPECIFICITY; DERIVATIVES; PROGRESSION; EXPRESSION; SULFATE;
D O I
10.3390/cancers13122959
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary Heparanase is an endoglycosidase that plays a critical role in tumor progression and metastasis. The expression of heparanase in the tumor microenvironment is positively correlated with the aggressiveness of the tumor and is associated with poor prognosis. In this study, we have demonstrated that a new triazole-thiadiazole-bearing small molecule showed good heparanase inhibition along with attenuation of tumor growth and metastasis. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with a small molecule that inhibits heparanase enzymatic activity. Given these encouraging results, studies are underway to better elucidate the mode of action and clinical significance of triazolo-thiadiazoles. Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo-thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.
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页数:17
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共 62 条
  • [1] Heparanase in Acute Kidney Injury
    Abassi, Zaid
    Goligorsky, M. S.
    [J]. HEPARANASE: FROM BASIC RESEARCH TO CLINICAL APPLICATIONS, 2020, 1221 : 685 - 702
  • [2] Heparanase, Heparan Sulfate and Viral Infection
    Agelidis, Alex
    Shukla, Deepak
    [J]. HEPARANASE: FROM BASIC RESEARCH TO CLINICAL APPLICATIONS, 2020, 1221 : 759 - 770
  • [3] Differential Therapeutic Effects of Anti-VEGF-A Antibody in Different Tumor Models: Implications for Choosing Appropriate Tumor Models for Drug Testing
    Alishekevitz, Dror
    Bril, Rotem
    Loven, David
    Miller, Valeria
    Voloshin, Tali
    Gingis-Velistki, Svetlana
    Fremder, Ella
    Scherer, Stefan J.
    Shaked, Yuval
    [J]. MOLECULAR CANCER THERAPEUTICS, 2014, 13 (01) : 202 - 213
  • [4] Identification of Novel Class of TriazoloThiadiazoles as Potent Inhibitors of Human Heparanase and their Anticancer Activity
    Baburajeev, C. P.
    Mohan, Chakrabhavi Dhananjaya
    Rangappa, Shobith
    Mason, Daniel J.
    Fuchs, Julian E.
    Bender, Andreas
    Barash, Uri
    Vlodavsky, Israel
    Basappa
    Rangappa, Kanchugarakoppal S.
    [J]. BMC CANCER, 2017, 17
  • [5] Heparanase enhances myeloma progression via CXCL10 downregulation
    Barash, U.
    Zohar, Y.
    Wildbaum, G.
    Beider, K.
    Nagler, A.
    Karin, N.
    Ilan, N.
    Vlodavsky, I.
    [J]. LEUKEMIA, 2014, 28 (11) : 2178 - 2187
  • [6] Heparanase promotes glioma progression via enhancing CD24 expression
    Barash, Uri
    Spyrou, Argyris
    Liu, Pei
    Vlodaysky, Euvgeni
    Zhu, Chenchen
    Luo, Juanjuan
    Su, Dongsheng
    Ilhan, Neta
    Forsberg-Nilsson, Karin
    Vlodaysky, Israel
    Yang, Xiaojun
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2019, 145 (06) : 1596 - 1608
  • [7] Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications
    Barash, Uri
    Lapidot, Moshe
    Zohar, Yaniv
    Loomis, Cynthia
    Moreira, Andre
    Feld, Sari
    Goparaju, Chandra
    Yang, Haining
    Hammond, Edward
    Zhang, Ganlin
    Li, Jin-Ping
    Ilan, Neta
    Nagler, Arnon
    Pass, Harvey I.
    Vlodavsky, Israel
    [J]. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2018, 110 (10):
  • [8] A small oxazine compound as an anti-tumor agent: A novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-α
    Basappa
    Murugan, Sengottuvelan
    Kavitha, Chandagirikoppal V.
    Purushothaman, Anurag
    Nevin, Kottayath G.
    Sugahara, Kazuyuki
    Rangappa, Kanchugarakoppal S.
    [J]. CANCER LETTERS, 2010, 297 (02) : 231 - 243
  • [9] Anti-tumor and anti-angiogenic activity of novel hydantoin derivatives: Inhibition of VEGF secretion in liver metastatic osteosarcoma cells
    Basappa
    Kumar, C. S. Ananda
    Swamy, S. Nanjunda
    Sugahara, Kazuyuki
    Rangappa, Kanchugarakoppal S.
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (14) : 4928 - 4934
  • [10] Remodelling the extracellular matrix in development and disease
    Bonnans, Caroline
    Chou, Jonathan
    Werb, Zena
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2014, 15 (12) : 786 - 801