Peptide For Treatment Of Cancer Research Articles

Peptide-Based Therapeutics in Cancer Therapy.

A monster called cancer is still one of the most challenging human problems and one of the leading causes of death in the world. Different types of treatment methods are used for cancer therapy; however, there are challenges such as high cost and harmful side effects in using these methods. Recent years have witnessed a surge in the development of therapeutic peptides for a wide range of diseases, notably cancer. Peptides are preferred over antibiotics, radiation therapy, and chemotherapy in the treatment of cancer due to a number of aspects, including flexibility, easy modification, low immunogenicity, and inexpensive cost of production. The use of therapeutic peptides in cancer treatment is a novel and intriguing strategy. These peptides provide excellent prospects for targeted drug delivery because of their high selectivity, specificity, small dimensions, good biocompatibility, and simplicity of modification. Target specificity and minimal toxicity are benefits of therapeutic peptides. Additionally, peptides can be used to design antigens or adjuvants for vaccine development. Here, types of therapeutic peptides for cancer therapy will be discussed, such as peptide-based cancer vaccines and tumor-targeting peptides (TTP) and cell-penetrating peptides (CPP).

Utilization of macrocyclic peptides to target protein-protein interactions in cancer.

Protein-protein interactions (PPIs) play vital roles in normal cellular processes. Dysregulated PPIs are involved in the process of various diseases, including cancer. Thus, these PPIs may serve as potential therapeutic targets in cancer treatment. However, despite rapid advances in small-molecule drugs and biologics, it is still hard to target PPIs, especially for those intracellular PPIs. Macrocyclic peptides have gained growing attention for their therapeutic properties in targeting dysregulated PPIs. Macrocyclic peptides have some unique features, such as moderate sizes, high selectivity, and high binding affinities, which make them good drug candidates. In addition, some oncology macrocyclic peptide drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. Here, we reviewed the recent development of macrocyclic peptides in cancer treatment. The opportunities and challenges were also discussed to inspire new perspectives.

Cell‐penetrating peptides for cancer treatment: Current state and future directions

AbstractHow to efficiently deliver therapeutic agents into cancer cells is a knotty problem for researchers. Over the past 30 years, the use of cell‐penetrating peptides (CPPs) to facilitate intracellular cargo delivery has received extensive attention. Encouraged by their robust membrane permeability and satisfactory biocompatibility, various CPPs have been applied to construct anticancer drugs. However, owing to some unsolved problems, such as lack of cell selectively, short circulation time, and poor in vivo stability, no CPP has been approved by the Food and Drug Administration so far. Thus, further efforts are urgently needed to solve these problems. In this commentary, we discuss the current state and future directions of CPPs in the field of cancer therapy.

Rational Design of Self-Assembled Mitochondria-Targeting Lytic Peptide Conjugates with Enhanced Tumor Selectivity.

Membrane lytic peptides (MLP) are widely explored as cellular delivery vehicles or antitumor/antibacterial agents. However, the poor selectivity between cancer and normal cells slims their prospects as potential anti-tumor drugs. Herein, we have developed a rationally designed self-assembly strategy to enhance tumor selectivity of MLP-based conjugates, incorporating a hydrophobic triphenylphosphonium (TPP) group for mitochondria targeting, and a hydrophilic arginine-glycine-aspartic acid (RGD) sequence targeting integrins. The self-assembly nanoparticles can enhance the stability of the peptides in vitro plasma and be endocytosed selectively into the cancer cells. The histidine-rich lytic peptide component assists the disruption of endosomal/lysosomal membranes and subsequent the mitochondria membrane, which leads to apoptosis. This rational design of MLP-based conjugates provides a practical strategy to increase the application prospects of lytic peptides in cancer treatment.

Design of Polymeric Carriers for Intracellular Peptide Delivery in Oncology Applications.

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.

Nanoscale Melittin@Zeolitic Imidazolate Frameworks for Enhanced Anticancer Activity and Mechanism Analysis.

The cytolytic peptide melittin (MLT) is an important candidate of anticancer drug owing to its hemolytic properties. Nevertheless, its clinical applications are severely restricted as a result of its nonspecific toxicities like hemolysis. In this work, we reported MLT-loaded zeolitic imidazolate framework-8 (MLT@ZIF-8) nanoparticles (NPs). The formed MLT@ZIF-8 NPs not only possess excellent stability but also efficiently inhibit the hemolysis bioactivity of MLT. Confocal scanning imaging and cytotoxicity experiments revealed that as-synthesized MLT@ZIF-8 NPs exhibit enhanced cellular uptake and cytotoxicity toward cancer cells compared to MLT. The mechanism is well investigated by a series of transcriptome analysis, which indicates that MLT@ZIF-8 NPs can regulate the expression of 3383 genes, and the PI3K/Akt-regulated p53 pathway is involved in MLT@ZIF-8 NPs induced A549 cells apoptosis. Finally, MLT@ZIF-8 NPs exhibit enhanced antitumor activity than free MLT in vivo, while no obvious systemic toxicity has been found. This work emphasizes the great potential of utilizing MOF as a simple and efficient nanoplatform for deliverying cytolytic peptides in cancer treatment, and also the investigation on the antitumor mechanism could provide theoretical support for clinical usage of MLT.

The Potential Use of Peptides in Cancer Treatment.

Conventional chemotherapeutic drugs have significant limitations. For example, tumors may develop resistance, cancers may relapse after treatment, and the drugs may induce secondary malignancies in the treatment of metastatic cancer. There is still a great need for drugs that are able to destroy cancer cells selectively, that is, to effectively treat slow-growing and dormant cells without being affected by chemoresistance mechanisms. A growing number of studies indicate that peptides may be beneficial for drug discovery and development. Peptides offer minimal immunogenicity, excellent tissue penetrability, low-cost manufacturability, and ease of modification for enhancing in vivo stability and biological activity, properties which make them ideal candidates for cancer treatment. This review highlights recent advances in and future prospects for the application of peptides as therapeutic agents for cancer therapy. We discuss the application of peptides in cancer therapy, alone and in combination with other peptides or small-molecule chemotherapeutic drugs, for use in targeted cancer therapy. Furthermore, we consider the use of peptides as a carrier for targeted molecular imaging in the diagnosis and follow-up treatment of cancer. This account also reviews the challenges of using peptide drugs and ways to overcome these limitations. The results obtained in studies presented in this paper indicate that peptides are promising candidates for targeted cancer therapy.

Tumor-Targeting Peptides: Ligands for Molecular Imaging and Therapy.

The aberrant proliferation of tumor cells and abundant vasculature in tumor tissues are closely correlated with receptors that are specifically dysregulated in tumor cells. These tumor-associated targets are critical in early diagnosis and therapy selection. Ligands such as antibodies, proteins, polypeptides and polysaccharides that specifically bind to these targets can significantly improve the detection and cure rate when used as tumor imaging probes or anti-tumor agents. Compared to other targeting ligands, peptides have attracted increasingly more attention in tumor diagnostics and therapeutics because of their small sizes, high affinity, stability, ease of modification and low immunogenicity. Several peptide-based imaging probes and therapeutic agents have already been used in clinical trials. This review summarizes some of the tumor-associated targets and their corresponding peptides, as well as the potential of these peptides in cancer treatment.

A Novel Hybrid Sequence-Based Model for Identifying Anticancer Peptides.

Cancer is a serious health issue worldwide. Traditional treatment methods focus on killing cancer cells by using anticancer drugs or radiation therapy, but the cost of these methods is quite high, and in addition there are side effects. With the discovery of anticancer peptides, great progress has been made in cancer treatment. For the purpose of prompting the application of anticancer peptides in cancer treatment, it is necessary to use computational methods to identify anticancer peptides (ACPs). In this paper, we propose a sequence-based model for identifying ACPs (SAP). In our proposed SAP, the peptide is represented by 400D features or 400D features with g-gap dipeptide features, and then the unrelated features are pruned using the maximum relevance-maximum distance method. The experimental results demonstrate that our model performs better than some existing methods. Furthermore, our model has also been extended to other classifiers, and the performance is stable compared with some state-of-the-art works.

An in silico approach to design peptide mimetics based on docking and molecular dynamics simulation of EGFR–matuzumab complex

Epidermal growth factor receptor (EGFR) plays an essential role in anticancer therapy. Matuzumab is an antibody for the treatment of colorectal, lung and stomach cancer. Matuzumab binds efficiently to EGFR and blocks its phosphorylation. The recent clinical successes have established application of peptides for cancer treatment. The present contribution introduces an in silico approach to design peptides based on molecular dynamics simulation (MDs) of the matuzumab-EGFR complex in water environment. Moreover, principal component analysis has been used to select multiple conformations of the complex in MDs for designing the peptides. The paratope and epitope in each conformation of the complex were determined, and the alanine scanning was used to identify the hot spots of EGFR conformers. The conformations of the peptides were optimized using PEP-FOLD server and MDs. The selected conformations were analyzed in a docking study to realize the binding site of the EGFR. Finally, pharmokinetics properties of the peptides were calculated. The designed oligopeptides were EWRSYYYWH, YYYWHNEWN, YYYWHNEWS and HNHSRNYGS with a higher affinity to the EGFR relative to the previously reported peptides. The newly designed peptides were investigated for their in vivo toxicities on rats, and all of them were non-toxic.

The CT20 peptide: More than a Piece of Bax

Use of cytotoxic peptides for cancer treatment is an emerging therapeutic direction with promising potential; however, in many instances the intracellular actions of these peptides remain unknown. Finding ways to systematically decipher the intercellular targets and functions of rationally designed or endogenously sourced therapeutic peptides to better define clinical use is a significant challenge that needs to be addressed. Here we describe our recent results outlining the activity of CT20p, a peptide derived from the pro-apoptotic protein Bax, which specifically kills metastatic cancer cells but not normal epithelial cells. Using breast cancer as a model system to test the peptide, we found that CT20p can be delivered to cells by polymeric hyperbranched nanoparticles and that, once intracellular, has profound effects on cytosolic proteins and organelles in a cancer-specific fashion that are different from the parent protein. In cancer cells, CT20p localizes to the mitochondria, forms pores in mitochondrial-like membranes, alters mitochondrial movement and membrane polarization, and impairs cytoskeletal reorganization, leading to cell detachment and death. Further, we discuss our strategy for determining the molecular actions of CT20p that could help inform the activities of other currently available antimicrobial and anticancer therapeutic peptides.

Cancer Treatment Using Peptides: Current Therapies and Future Prospects

This paper discusses the role of peptides in cancer therapy with special emphasis on peptide drugs which are already approved and those in clinical trials. The potential of peptides in cancer treatment is evident from a variety of different strategies that are available to address the progression of tumor growth and propagation of the disease. Use of peptides that can directly target cancer cells without affecting normal cells (targeted therapy) is evolving as an alternate strategy to conventional chemotherapy. Peptide can be utilized directly as a cytotoxic agent through various mechanisms or can act as a carrier of cytotoxic agents and radioisotopes by specifically targeting cancer cells. Peptide-based hormonal therapy has been extensively studied and utilized for the treatment of breast and prostate cancers. Tremendous amount of clinical data is currently available attesting to the efficiency of peptide-based cancer vaccines. Combination therapy is emerging as an important strategy to achieve synergistic effects in fighting cancer as a single method alone may not be efficient enough to yield positive results. Combining immunotherapy with conventional therapies such as radiation and chemotherapy or combining an anticancer peptide with a nonpeptidic cytotoxic drug is an example of this emerging field.

Abstract LB-292: Nucleolin targeting oncolytic peptide for treatment of cancer

Abstract New targeted cancer therapies under development deliver cytotoxic molecules to cancer cells via specific binding of ligands to molecules or receptors that are over-expressed on the surface of cancer cells. Nucleolin is a protein that is over-expressed on the surface and cytoplasm of cancer and endothelial cells compared to normal cells. EP-302 consists of a nucleolin binding moiety conjugated to a novel lytic peptide called CLIP-71 to target and destroy cells that express nucleolin on their surfaces. It was tested in vitro in 20 human cancer cell lines (including breast, endometrial, ovarian, pancreatic, prostate, colon, lung and hematological malignancies). Nucleolin negative HS27 human fibroblast and 3T3 cells were used as negative controls. Cells were cultured in the presence of various concentrations (0.0001-100 M) of EP-302 or unconjugated CLIP-71 for 0.25 to 24h. Hemolytic effects of EP-302 on human red blood cells, plasma stability and tolerability in mice were also tested. Viability was measured by formazan conversion assays. In addition, specific binding to cell surface nucleolin was determined by immunohistochemistry in cell lines western blot analysis from membrane preparations and tumor sections. In vivo efficacy of EP-302 was conducted in female and male nude mice implanted with MDA-MB-435S or PC-3 cells. Treatment groups were: saline controls, 0.02, 0.2 and 1 mg/kg (PC-3 xenografts N=16 per group) and 0.2 and 1 mg/kg (MDA-MB-435 xenografts, N=10 per group). Mice were treated weekly for 3 weeks via a bolus injection into the lateral tail vein. Results show that EP-302 caused a dose-dependent cell killing after 24h incubation in MDA-MB-435S (IC50 - 1.8 M) and PC-3 (IC50 - 3.3 M) cells and 53 M in nucleolin negative HS27 and 3 T3 cells. Sixteen human cancer cell lines had IC50 values of 0.5-6.4 M. Nucleolin binding peptide F3 inhibited the cytotoxicity of EP-302 indicating that the cytotoxic effects of EP-302 are mediated via binding to nucleolin. There was no hemolytic activity at concentrations <1000 M and plasma stability studies showed that > 60% bioactivity was present after 2 h of incubation. Studies with fluorecein-labeled EP-302 demonstrated specific binding and cell destruction within 30 minutes. The maximal tolerated dose in nude mice was 8 mg/kg EP-302 after daily repeated injections for 5 days. In vivo efficacy studies resulted in significant (p<0.0035) tumor regression for PC-3 xenograft at doses of 0.02, 0.2 and 1 mg/kg and increased survival of the mice. Tumor regression was also found in the MDA-MB-435S xenograft (p<0.0001) at all doses tested. Histological evaluation of treated tumors showed that cell killing was primarily by necrosis. These results indicate that EP-302 selectively targets and kills only cancer cells that have surface nucleolin. They demonstrate that EP-302 is a potential therapy for cancers in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-292.

Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer

Immunogenicity caused by the use of nonhuman enzymes in antibody-directed enzyme prodrug therapy has limited its clinical application. To overcome this problem, we have developed a mutant human purine nucleoside phosphorylase, which, unlike the wild-type enzyme, accepts (deoxy)adenosine-based prodrugs as substrates. Among the different mutants of human purine nucleoside phosphorylase tested, a double mutant with amino acid substitutions E201Q:N243D (hDM) is the most efficient in cleaving (deoxy)adenosine-based prodrugs. Although hDM is capable of using multiple prodrugs as substrates, it is most effective at cleaving 2-fluoro-2'-deoxyadenosine to a cytotoxic drug. To target hDM to the tumor site, the enzyme was fused to an anti-HER-2/neu peptide mimetic (AHNP). Treatment of HER-2/neu-expressing tumor cells with hDM-AHNP results in cellular localization of enzyme activity. As a consequence, harmless prodrug is converted to a cytotoxic drug in the vicinity of the tumor cells, resulting in tumor cell apoptosis. Unlike the nonhuman enzymes, the hDM should have minimal immunogenicity when used in antibody-directed enzyme prodrug therapy, thus providing a novel promising therapeutic agent for the treatment of tumors.