The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor

Abdelhadi Rebbaa, Fei Chu, Thangirala Sudha, Christine A. Gallati, Usawadee Dier, Evgeny Dyskin, Murat Yalcin, Christine Bianchini, Olfat Shaker, Shaker A. Mousa

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Increased neovasculature and resistance to chemotherapy are hallmarks of aggressive cancer; therefore, the development of approaches to simultaneously inhibit these two processes is highly desirable. Previous findings from our laboratory have demonstrated that cathepsin L plays a key role in the development of drug resistance in cancer, and that its inhibition reversed this phenomenon. The goal of the present study was to determine whether targeting cathepsin L would inhibit angiogenesis. For this, the effects of a specific cathepsin L inhibitor, Napsul-Ile-Trp-CHO (NSITC), were tested in vitro on endothelial cell proliferation and interaction with the extracellular matrix, and also in vivo, by measuring its effect on angiogenesis in the chick chorioallantoic membrane (CAM) and mouse matrigel models. The results indicated that NSITC readily inhibits the proliferation of endothelial cells by inducing cell cycle arrest at the G0/G1 phase, and suppresses cell adhesion to different substrates. Investigation of the underlying mechanism(s) indicated that NSITC was able to reduce expression of the adhesion molecule αVβ3 integrin, inhibit cathepsin L-mediated degradation of the extracellular matrix, and disrupt secretion of the pro-angiogenic factors fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). NSITC demonstrated potent efficacy in inhibiting growth factor- and tumor mediated-angiogenesis in the CAM and mouse matrigel models of angiogenesis. The anti-angiogenic effects of NSITC resulted in inhibition of tumor growth in the CAM and in nude mouse xenograft models. Together, these findings provide evidence that cathepsin L plays an important role in angiogenesis and suggest that NSITC represents a potential drug for the treatment of aggressive cancer.

Original languageEnglish (US)
Pages (from-to)4473-4481
Number of pages9
JournalAnticancer Research
Volume29
Issue number11
StatePublished - Nov 1 2009

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Cathepsin L
Chorioallantoic Membrane
Neoplasms
Extracellular Matrix
Endothelial Cells
Cell Cycle Resting Phase
Fibroblast Growth Factors
Angiogenesis Inducing Agents
G1 Phase
Cell Cycle Checkpoints
Drug Resistance
Heterografts
Nude Mice
Cell Adhesion
Integrins
Cell Communication
Vascular Endothelial Growth Factor A
Napsul-Ile-Trp-CHO
Intercellular Signaling Peptides and Proteins
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Rebbaa, A., Chu, F., Sudha, T., Gallati, C. A., Dier, U., Dyskin, E., ... Mousa, S. A. (2009). The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor. Anticancer Research, 29(11), 4473-4481.
Rebbaa, Abdelhadi ; Chu, Fei ; Sudha, Thangirala ; Gallati, Christine A. ; Dier, Usawadee ; Dyskin, Evgeny ; Yalcin, Murat ; Bianchini, Christine ; Shaker, Olfat ; Mousa, Shaker A. / The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor. In: Anticancer Research. 2009 ; Vol. 29, No. 11. pp. 4473-4481.
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Rebbaa, A, Chu, F, Sudha, T, Gallati, CA, Dier, U, Dyskin, E, Yalcin, M, Bianchini, C, Shaker, O & Mousa, SA 2009, 'The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor', Anticancer Research, vol. 29, no. 11, pp. 4473-4481.

The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor. / Rebbaa, Abdelhadi; Chu, Fei; Sudha, Thangirala; Gallati, Christine A.; Dier, Usawadee; Dyskin, Evgeny; Yalcin, Murat; Bianchini, Christine; Shaker, Olfat; Mousa, Shaker A.

In: Anticancer Research, Vol. 29, No. 11, 01.11.2009, p. 4473-4481.

Research output: Contribution to journalArticle

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AU - Rebbaa, Abdelhadi

AU - Chu, Fei

AU - Sudha, Thangirala

AU - Gallati, Christine A.

AU - Dier, Usawadee

AU - Dyskin, Evgeny

AU - Yalcin, Murat

AU - Bianchini, Christine

AU - Shaker, Olfat

AU - Mousa, Shaker A.

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N2 - Increased neovasculature and resistance to chemotherapy are hallmarks of aggressive cancer; therefore, the development of approaches to simultaneously inhibit these two processes is highly desirable. Previous findings from our laboratory have demonstrated that cathepsin L plays a key role in the development of drug resistance in cancer, and that its inhibition reversed this phenomenon. The goal of the present study was to determine whether targeting cathepsin L would inhibit angiogenesis. For this, the effects of a specific cathepsin L inhibitor, Napsul-Ile-Trp-CHO (NSITC), were tested in vitro on endothelial cell proliferation and interaction with the extracellular matrix, and also in vivo, by measuring its effect on angiogenesis in the chick chorioallantoic membrane (CAM) and mouse matrigel models. The results indicated that NSITC readily inhibits the proliferation of endothelial cells by inducing cell cycle arrest at the G0/G1 phase, and suppresses cell adhesion to different substrates. Investigation of the underlying mechanism(s) indicated that NSITC was able to reduce expression of the adhesion molecule αVβ3 integrin, inhibit cathepsin L-mediated degradation of the extracellular matrix, and disrupt secretion of the pro-angiogenic factors fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). NSITC demonstrated potent efficacy in inhibiting growth factor- and tumor mediated-angiogenesis in the CAM and mouse matrigel models of angiogenesis. The anti-angiogenic effects of NSITC resulted in inhibition of tumor growth in the CAM and in nude mouse xenograft models. Together, these findings provide evidence that cathepsin L plays an important role in angiogenesis and suggest that NSITC represents a potential drug for the treatment of aggressive cancer.

AB - Increased neovasculature and resistance to chemotherapy are hallmarks of aggressive cancer; therefore, the development of approaches to simultaneously inhibit these two processes is highly desirable. Previous findings from our laboratory have demonstrated that cathepsin L plays a key role in the development of drug resistance in cancer, and that its inhibition reversed this phenomenon. The goal of the present study was to determine whether targeting cathepsin L would inhibit angiogenesis. For this, the effects of a specific cathepsin L inhibitor, Napsul-Ile-Trp-CHO (NSITC), were tested in vitro on endothelial cell proliferation and interaction with the extracellular matrix, and also in vivo, by measuring its effect on angiogenesis in the chick chorioallantoic membrane (CAM) and mouse matrigel models. The results indicated that NSITC readily inhibits the proliferation of endothelial cells by inducing cell cycle arrest at the G0/G1 phase, and suppresses cell adhesion to different substrates. Investigation of the underlying mechanism(s) indicated that NSITC was able to reduce expression of the adhesion molecule αVβ3 integrin, inhibit cathepsin L-mediated degradation of the extracellular matrix, and disrupt secretion of the pro-angiogenic factors fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). NSITC demonstrated potent efficacy in inhibiting growth factor- and tumor mediated-angiogenesis in the CAM and mouse matrigel models of angiogenesis. The anti-angiogenic effects of NSITC resulted in inhibition of tumor growth in the CAM and in nude mouse xenograft models. Together, these findings provide evidence that cathepsin L plays an important role in angiogenesis and suggest that NSITC represents a potential drug for the treatment of aggressive cancer.

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Rebbaa A, Chu F, Sudha T, Gallati CA, Dier U, Dyskin E et al. The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor. Anticancer Research. 2009 Nov 1;29(11):4473-4481.