Two peptides derived from ras-p21 induce either phenotypic reversion or tumor cell necrosis of ras-transformed human cancer cells

Adler, Victor; Bowne, Wilbur B.; Ikram, M. Kamran; Michl, Josef; Friedman, Fred K.; Chin, Edwin; Zenilman, Michael E.; Pincus, Matthew R.

doi:10.1007/s00280-007-0630-5

Cited by 6 publications

(9 citation statements)

References 22 publications

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“…The same authors point out that the region comprised between amino acids 55 and 71 of Ras make also contact with GAP and SOS proteins. Pincus and co-workers affirm that their peptides PCN-7 (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47) and PCN-2 (96-110) block interaction with Raf and have an anti-tumor effect on cell lines. They also affirm that both peptides induce phenotypic reversion of the HT-1080 cell line to non-transformed cells but cause tumor cell necrosis on MIA-PaCa2 cell line.…”

Section: Raf-binding Assays On Cellulose-bound Peptides Containing Ras Sequencesmentioning

confidence: 98%

“…They speculate that PCN-2 might block oncogenic Ras by inhibiting its interaction with JNK. PCN-7 could block the interaction of oncogenic Ras with Raf [38,39]. They suggest that both oncogenic and wild type Ras requires Raf activation, and assume, without demonstration, that each Ras protein interacts with Raf in different ways, resulting in differential activation of downstream kinases.…”

Section: Raf-binding Assays On Cellulose-bound Peptides Containing Ras Sequencesmentioning

confidence: 99%

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Identification of ras/raf binding site and design of interfering peptide with potential clinical application

Tian¹,

Zhang²,

Némati³

et al. 2016

Integr Mol Med

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Despite intensive effort, no effective pharmacological inhibitors of the Ras oncoprotein have been reached the clinic given the impression that Ras proteins are undruggable. However, progresses have been made in several directions to manipulate Ras.In this manuscript, we describe a novel and promising approach for specifically targeting the Ras/Raf interaction. We have identified the amino acid sequence involved in the binding of Ras to Raf. The amino acids of the binding site were coupled to an optimized penetrating peptide in order to generate a chimeric peptide, Mut3DPT-Ras, able to penetrate the cells and target Ras/Raf interaction. We demonstrate that this protease-resistant peptide has an in vitro apoptotic effect on several cancer cell lines and on primary cells isolated from chronic lymphocytic leukemia (CLL) as well as an antitumoral effect on chronic lymphocytic leukemialike and lymphoma xenograft model. The new generated peptide allows the modulation of the Ras/Raf interaction and might have a potential as a new therapeutic approach for cancer treatment.

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Section: Raf-binding Assays On Cellulose-bound Peptides Containing Ras Sequencesmentioning

confidence: 98%

Section: Raf-binding Assays On Cellulose-bound Peptides Containing Ras Sequencesmentioning

confidence: 99%

Identification of ras/raf binding site and design of interfering peptide with potential clinical application

Tian¹,

Zhang²,

Némati³

et al. 2016

Integr Mol Med

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“…Kanovsky et al [108] found that two ras-p21 peptides PNC-7 and PNC-2 (96–110 residues) induced phenotypic reversion of both ras-transformed rat pancreatic cancer cells (TUC-3) to their untransformed phenotypes. These peptides were linked to penetratin a CPP; which induced the phenotypic reversion of ras-transformed human fibrosarcoma cells (HT-1080) to its untransformed phenotype [109]. Both peptides induced the death of MIA-PaCa-2 human pancreatic cancer cells by inhibiting ras-p21 phosphorylation [109], however it did not cause these cells to undergo phenotypic reversion.…”

Section: Therapeutic Peptides Target Signal Transduction Pathwaysmentioning

confidence: 99%

“…These peptides were linked to penetratin a CPP; which induced the phenotypic reversion of ras-transformed human fibrosarcoma cells (HT-1080) to its untransformed phenotype [109]. Both peptides induced the death of MIA-PaCa-2 human pancreatic cancer cells by inhibiting ras-p21 phosphorylation [109], however it did not cause these cells to undergo phenotypic reversion.…”

Section: Therapeutic Peptides Target Signal Transduction Pathwaysmentioning

confidence: 99%

Evaluation of the use of therapeutic peptides for cancer treatment

2017

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Cancer along with cardiovascular disease are the main causes of death in the industrialised countries around the World. Conventional cancer treatments are losing their therapeutic uses due to drug resistance, lack of tumour selectivity and solubility and as such there is a need to develop new therapeutic agents. Therapeutic peptides are a promising and a novel approach to treat many diseases including cancer. They have several advantages over proteins or antibodies: as they are (a) easy to synthesise, (b) have a high target specificity and selectivity and (c) have low toxicity. Therapeutic peptides do have some significant drawbacks related to their stability and short half-life. In this review, strategies used to overcome peptide limitations and to enhance their therapeutic effect will be compared. The use of short cell permeable peptides that interfere and inhibit protein-protein interactions will also be evaluated.

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“…Therapeutic peptides have been designed to inhibit MAPK pathways. Two ras-p21 peptides, (PNC-7 and PNC-2, both derived from Ras gene encoded 21 protein), were conjugated with the CCP penetratin to block oncogenic ras-p21, inducing the phenotypic reversion of ras-transformed human fibrosarcoma cells (HT-1080) to the untransformed phenotype . In another example, c-Jun amino terminal kinase (JNK) peptide inhibitors, derived from the JNK interacting protein (JIP), were conjugated to CCPs ( e.g.…”

Section: Peptide Therapeutics In Cancer Therapymentioning

confidence: 99%

Design of Polymeric Carriers for Intracellular Peptide Delivery in Oncology Applications

Sylvestre

Prossnitz

et al. 2021

Chem. Rev.

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In recent decades, peptides, which can possess high potency, excellent selectivity, and low toxicity, have emerged as promising therapeutics for cancer applications. Combined with an improved understanding of tumor biology and immuno-oncology, peptides have demonstrated robust antitumor efficacy in preclinical tumor models. However, the translation of peptides with intracellular targets into clinical therapies has been severely hindered by limitations in their intrinsic structure, such as low systemic stability, rapid clearance, and poor membrane permeability, that impede intracellular delivery. In this Review, we summarize recent advances in polymer-mediated intracellular delivery of peptides for cancer therapy, including both therapeutic peptides and peptide antigens. We highlight strategies to engineer polymeric materials to increase peptide delivery efficiency, especially cytosolic delivery, which plays a crucial role in potentiating peptide-based therapies. Finally, we discuss future opportunities for peptides in cancer treatment, with an emphasis on the design of polymer nanocarriers for optimized peptide delivery.

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Two peptides derived from ras-p21 induce either phenotypic reversion or tumor cell necrosis of ras-transformed human cancer cells

Abstract: We conclude that these peptides block tumor but not normal cell growth likely by blocking oncogenic ras-p21-induced phosphorylation of JNK, an essential step on the oncogenic ras-p21-protein pathway. These peptides are therefore promising as possible anti-tumor agents.

Cited by 6 publications

References 22 publications

Identification of ras/raf binding site and design of interfering peptide with potential clinical application

Identification of ras/raf binding site and design of interfering peptide with potential clinical application

Evaluation of the use of therapeutic peptides for cancer treatment

Design of Polymeric Carriers for Intracellular Peptide Delivery in Oncology Applications

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