Targeting Heparanase in Cancer: Inhibition by Synthetic, Chemically Modified, and Natural Compounds

Mohan, Chakrabhavi Dhananjaya; Hari, Swetha; Preetham, Habbanakuppe D.; Rangappa, Shobith; Barash, Uri; Ilan, Neta; Nayak, S. Chandra; Gupta, Vijai Kumar; Basappa, Basappa; Vlodavsky, Israël; Rangappa, Kanchugarakoppal S.

doi:10.1016/j.isci.2019.04.034

Cited by 84 publications

(73 citation statements)

References 202 publications

(322 reference statements)

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“…Moreover, studies incriminate peroxides by stimulating pathological angiogenesis. In this respect, different researchers have demonstrated in their studies that antioxidants such as catechins [34], resveratrol [35], polyphenols [36], flavonoids [37], nutritional components, and also synthetic compounds [38] are able to inhibit angiogenesis. In addition, our research is focused on the antioxidant action of chitosan-sulfonamide derivatives (CLA-CLD) on the one hand, but also on the potential of nanostructures to inhibit angiogenesis through the large contact surface that they provide.…”

Section: Discussionmentioning

confidence: 99%

Designing of Chitosan Derivatives Nanoparticles with Antiangiogenic Effect for Cancer Therapy

et al. 2020

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Angiogenesis is a physiological process involving the growth of new blood vessels, which provides oxygen and required nutrients for the development of various pathological conditions. In a tumor microenvironment, this process upregulates the growth and proliferation of tumor cells, thus any stage of angiogenesis can be a potential target for cancer therapies. In the present study, chitosan and his derivatives have been used to design novel polymer-based nanoparticles. The therapeutic potential of these newly designed nanoparticles has been evaluated. The antioxidant and MTT assays were performed to know the antioxidant properties and their biocompatibility. The in vivo antiangiogenic properties of the nanoparticles were evaluated by using a chick Chorioallantoic Membrane (CAM) model. The obtained results demonstrate that chitosan derivatives-based nanostructures strongly enhance the therapeutic effect compared to chitosan alone, which also correlates with antitumor activity, demonstrated by the in vitro MTT assay on human epithelial cervical Hep-2 tumor cells. This study opens up new direction for the use of the chitosan derivatives-based nanoparticles for designing of antiangiogenic nanostructured materials, for future cancer therapy.While stimulation of angiogenesis in cancer leads to metastasis, the anti-angiogenic therapy proved to be an important approach against tumor growth. In this respect, it is a well-known fact that the consumption of antioxidants can be recommended to achieve the inhibition of angiogenesis or reversal of unwanted cell-cell adherence [1]. Several studies have been conducted to investigate the connection between antioxidants and pathological angiogenesis, thus leading to mixed conclusions from studies that have been associated with a lower total cancer incidence with the use of antioxidants [2], to studies that have highlighted the lack of any benefit of using antioxidants on the incidence of cancer [3]. All these results are, for certain ones, closely related with the type of antioxidant included in the study (alpha tocopherol, beta-carotene, ascorbic acid) and the investigated tumor location and not least the investigated pharmaceutical formulation. In this context, the use of antioxidants in the form of nanoparticles could improve the efficiency of this therapy due to specific surface area of nanostructures [4], thereby ensuring better contact with cells that would increase the chances of pathological angiogenesis inhibition. However, to have more success in cancer therapy, more studies should be conducted in this direction.Chitosan is a natural cationic polymer exhibits three chemical reactive sites including a primary amine and two primary or secondary hydroxyl groups for further modification [5][6][7]. Nano/microparticles coated with chitosan, synthesized through different techniques for encapsulation (chemical, physical and mechanical techniques), are in continuous development, aiming at the entrapment of bioactive substances, enzymes, hormones, antimicrobial agents, vitamins, mi...

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Section: Discussionmentioning

confidence: 99%

Designing of Chitosan Derivatives Nanoparticles with Antiangiogenic Effect for Cancer Therapy

et al. 2020

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“…Glycol-splitting of unsubstituted uronic acids obtained by periodate oxidation and borohydride reduction has been applied to a variety of heparin derivatives and increased the flexibility of the molecules for a better interaction and inhibition of heparanase or growth factors. M402 (Necuparanib) is a glycol-split LMWH with reduced anticoagulant activity [170] that was found to reduce tumor burden in vivo in KPFMC pancreatic cancer mice model at a dose of 40 mg/kg/day and reduce AsPC-1 pancreatic cancer cell line proliferation and invasion in vitro in a 3D-culture model [171]. Boothello et al synthesized a non-saccharide compound, G2.2, which is structurally homogeneous and easy to obtain by chemical synthesis, as a mimetic of an HS hexasaccharide active on cancer stem cells.…”

Section: Targeting the Tumormentioning

confidence: 99%

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

2020

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This review comes as a part of the special issue “Emerging frontiers in GAGs and mimetics”. Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

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“…Heparanase has been considered a drug target for cancer and inflammation [39][40][41][42][43][44] . Nonetheless, only four saccharide-based inhibitors have been assessed in clinical trials 1,45 .…”

Section: Hadp-assisted High-throughput Inhibitor Screeningmentioning

confidence: 99%

Ultrasensitive small molecule fluorogenic probe for human heparanase

Schleyer

Bryan

et al. 2020

Preprint

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Heparanase is a critical enzyme involved in the remodeling of the extracellular matrix (ECM), and its elevated expression has been linked with diseases such as cancer and inflammation. The detection of heparanase enzymatic activity holds tremendous value in the study of the cellular microenvironment, and search of molecular therapeutics targeting heparanase, however, assays developed for this enzyme so far have suffered prohibitive drawbacks. Here we present an ultrasensitive fluorogenic small-molecule probe for heparanase enzymatic activity. The probe exhibits a 756-fold fluorescence turn-on response in the presence of human heparanase, allowing one-step detection of heparanase activity in real-time with a picomolar detection limit. The high sensitivity and robustness of the probe are exemplified in a high-throughput screening assay for heparanase inhibitors.Heparanase, an endo-β-glucuronidase of the glycoside hydrolase 79 (GH79) family 1,2 , is responsible for the cleavage of heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPG) 3 . These protein-polysaccharide conjugated macromolecules, abundantly expressed in the extracellular matrix (ECM), play an essential structural role in maintaining the ECM integrity.Moreover, the HS side chains bind to an array of biological effector molecules, such as growth factors, chemokines, and cytokines, thereby serving as their reservoir that can liberate the desired signaling molecules when needed.

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Targeting Heparanase in Cancer: Inhibition by Synthetic, Chemically Modified, and Natural Compounds

Cited by 84 publications

References 202 publications

Designing of Chitosan Derivatives Nanoparticles with Antiangiogenic Effect for Cancer Therapy

Designing of Chitosan Derivatives Nanoparticles with Antiangiogenic Effect for Cancer Therapy

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

Ultrasensitive small molecule fluorogenic probe for human heparanase

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