Cathepsin B and its inhibitor stefin A in brain tumors

Strojnik, Tadej; Zajc, Irena; Bervar, Aleš; Židanik, Boris; Golouh, Rastko; Kos, Janko; Dolenc, Vinko V.; Lah, Tamara T.

doi:10.1007/s004240000114

Cited by 35 publications

(7 citation statements)

References 3 publications

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“…Of the cysteine cathepsins, cathepsin B was co-expressed with stefin A in primary tumors and metastases, suggesting that stefin A suppressed metastasis via inhibition of cathepsin B. This was supportive of previous studies that demonstrate that a shift in equilibrium between cathepsin B and its endogenous inhibitor stefin A predicts poor survival outcomes (22, 23). …”

Section: Introductionsupporting

confidence: 87%

Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer

et al. 2012

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Metastasis to bone is a major cause of morbidity in breast cancer patients, emphasizing the importance of identifying molecular drivers of bone metastasis for new therapeutic targets. The endogenous cysteine cathepsin inhibitor stefin A is a suppressor of breast cancer metastasis to bone that is co-expressed with cathepsin B in bone metastases. In this study, we used the immunocompetent 4T1.2 model of breast cancer which exhibits spontaneous bone metastasis to evaluate the function and therapeutic targeting potential of cathepsin B in this setting of advanced disease. Cathepsin B abundancy in the model mimicked human disease, both at the level of primary tumors and matched spinal metastases. RNAi-mediated knockdown of cathepsin B in tumor cells reduced collagen I degradation in vitro and bone metastasis in vivo. Similarly, intraperitoneal administration of the highly selective cathepsin B inhibitor CA-074 reduced metastasis in tumor-bearing animals, a reduction that was not reproduced by the broad spectrum cysteine cathepsin inhibitor JPM-OEt. Notably, metastasis suppression by CA-074 was maintained in a late treatment setting, pointing to a role in metastatic outgrowth. Together, our findings established a pro-metastatic role for cathepsin B in distant metastasis and illustrated the therapeutic benefits of its selective inhibition in vivo.

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Section: Introductionsupporting

confidence: 87%

Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer

et al. 2012

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“…The malignant progression of the cancerous cells and tumour formation is exacerbated by reduced levels of the endogenous inhibitors used to regulate the cathepsin peptidases, such as cystatin C that regulates cathepsin B in cases of tongue cancer [35] and breast cancer [36]. Moreover, decreased levels of Stefin A and Stefin B are associated with breast, prostate, cervical and brain cancers [37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Targeting Secreted Protease/Anti-Protease Balance as a Vaccine Strategy against the Helminth Fasciola hepatica

et al. 2022

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The liver fluke Fasciola hepatica is an economically important global pathogen of humans and their livestock. To facilitate host invasion and migration, F. hepatica secretes an abundance of cathepsin peptidases but prevents excessive damage to both parasite and host tissues by co-secreting regulatory peptidase inhibitors, cystatins/stefins and Kunitz-type inhibitors. Here, we report a vaccine strategy aimed at disrupting the parasite’s protease/anti-protease balance by targeting these key inhibitors. Our vaccine cocktail containing three recombinant stefins (rFhStf-1, rFhStf-2, rFhStf-3) and a Kunitz-type inhibitor (rFhKT1) formulated in adjuvant Montanide 61VG was assessed in two independent sheep trials. While fluke burden was not reduced in either trial, in Trial 1 the vaccinated animals showed significantly greater weight gain (p < 0.05) relative to the non-vaccinated control group. In both trials we observed a significant reduction in egg viability (36–42%). Multivariate regression analyses showed vaccination and increased levels of IgG2 antibodies specific for the F. hepatica peptidase inhibitors were positive indicators for increased weight gain and levels of haemoglobin within the normal range at 16 weeks post-infection (wpi; p < 0.05). These studies point to the potential of targeting peptidase inhibitors as vaccine cocktails for fasciolosis control in sheep.

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“…It is non-immunogenic, non-toxic, and biodegradable by cathepsin B [18–20], an enzyme that is highly expressed in most tumor tissues [21–24]. In this manuscript we evaluated the anti-angiogenic effect on top of the known antitumor effect of polymer conjugate of PTX.…”

Section: Introductionmentioning

confidence: 99%

Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel

et al. 2011

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Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX, a polymer and an integrin-targeted moiety resulting in a polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a macromolecule, which passively targets the tumor tissue exploiting the enhanced permeability and retention effect, while extravasating via the leaky tumor neovasculature. The cyclic RGD peptidomimetic enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the αvβ3 integrin overexpressed on tumor endothelial and epithelial cells. This strategy is particularly valuable when tumors are well-vascularized, but they present poor vascular permeability. We show that PGA is enzymatically-degradable leading to PTX release under lysosomal acidic pH. PGA-PTX-E-[c(RGDfK)2] inhibited the growth of proliferating αvβ3-expressing endothelial cells and several cancer cells. We also showed that PGA-PTX-E-[c(RGDfK)2] blocked endothelial cells migration towards vascular endothelial growth factor; blocked capillary-like tube formation; and inhibited endothelial cells attachment to fibrinogen. Orthotopic studies in mice demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decrease in toxicity as compared with free PTX-treated mice.

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Cathepsin B and its inhibitor stefin A in brain tumors

Cited by 35 publications

References 3 publications

Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer

Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer

Targeting Secreted Protease/Anti-Protease Balance as a Vaccine Strategy against the Helminth Fasciola hepatica

Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel

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