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Anti-cancer Peptides and Peptide-Like Molecules

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 21950

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Special Issue Editors

Prof. Dr. Matthew R. Pincus

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Guest Editor

SUNY Downstate Medical Center Brooklyn, Brooklyn, NY, USA
Interests: anti-cancer peptides; molecular modeling of oncogenic and anti-oncogenic proteins; ras-p21 protein; p53 protein; PNC-27 anti-cancer peptide; membrane-bound HDM-2 protein; trans-membrane pore formation in cancer cells; ras-p21 peptides; selective blockade of oncogenic ras-p21 protein

Prof. Dr. Wilbur B. Bowne

E-Mail Website
Co-Guest Editor

Jefferson Medical Center, Philadelphia, PA, USA
Interests: anti-cancer peptides; cancer stem cells; PNC-27 anti-cancer peptide; co-localization with HDM-2 in cancer cell membrane; trans-membrane pores in cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Anticancer peptides are currently being found to be effective in inducing cancer cell death by tumor cell necrosis (e.g., PNC-27), apoptosis (e.g., p53 effector peptides), or in inducing reversion of tumor cells to the untransformed phenotype (e.g., ras-21 effector peptides). These peptides exert their effects on cancer cells and do not affect normal cells, giving them a major advantage over commonly used chemotherapeutic drugs. Although the half-lives of anticancer peptides are relatively short, they interact with their targets rapidly, resulting in cancer cell death or phenotypic reversion. Examples of these peptides include PNC-27, that contains the HDM-2 binding domain of p53 (residues 12–26) attached to an antennapedia leader sequence that binds to an HDM-2 isotype uniquely expressed in the membranes of cancer cells but not normal cells. When bound to HDM-2, this complex induces the formation of transmembrane pores, resulting in extrusion of intracellular contents and tumor cell necrosis. It has been found to obliterate highly metastatic pancreatic cancer in nude mice and to effectively treat human acute myelogenous leukemias in nude mice with no off-target effects. Other p53 peptides from its carboxyl terminal domain have been found to cause apoptosis or tumor cell necrosis of a variety of human tumors without affecting normal cells. Peptides designed from molecular modeling of oncogenic forms of ras-p21 have been found to induce phenotypic reversion of a variety of human and rat cancers by selectively blocking only the oncogenic ras-p21 pathway. This volume will discuss the antitumor effects of these new peptides and their mechanisms of action and suggest how they may be used clinically.

Prof. Dr. Wilbur B. Bowne
Dr. Matthew R. Pincus
Guest Editors

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Keywords

anti-cancer peptides
tumor cell necrosis
apoptosis
effector domains
p53 protein
ras-p21 protein
molecular modeling

Published Papers (9 papers)

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Research

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12 pages, 2426 KiB

Open AccessArticle

Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents

by Anna I. Miller, David Diaz, Bo Lin, Patryk K. Krzesaj, Sarah Ustoyev, Alfred Shim, Eugene J. Fine, Ehsan Sarafraz-Yazdi, Matthew R. Pincus and Richard D. Feinman

Biomedicines 2023, 11(9), 2515; https://doi.org/10.3390/biomedicines11092515 - 12 Sep 2023

Viewed by 1492

Abstract

The ketone bodies, sodium and lithium salts of acetoacetate (AcAc) and sodium 3-hydroxybutyrate (3-HB; commonly called beta-hydroxybutyrate) have been found to inhibit the proliferation of cancer cells. Previous studies have suggested that lithium itself may be an inhibiting agent but may be additive or synergistic with the effect of AcAc. We previously found that sodium acetoacetate (NaAcAc) inhibits the growth of human colon cancer cell line SW480. We report here similar results for several other cancer cell lines including ovarian, cervical and breast cancers. We found that NaAcAc does not kill cancer cells but rather blocks their proliferation. Similar inhibition of growth was seen in the effect of lithium ion alone (as LiCl). The effect of LiAcAc appears to be due to the combined effects of acetoacetate and the lithium ion. The ketone bodies, when given together with chemotherapeutic agents, rapamycin, methotrexate and the new peptide anti-cancer agent, PNC-27, substantially lowers their IC₅₀ values for cancer cell, killing suggesting that ketone bodies and ketogenic diets may be powerful adjunct agents in treating human cancers. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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21 pages, 2819 KiB

Open AccessArticle

Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo

by Robert L. Fine, Yuehua Mao, Dario Garcia-Carracedo, Gloria H. Su, Wanglong Qiu, Uri Hochfeld, Gwen Nichols, Yong-Liang Li, Richard D. Dinnen, Anthony Raffo and Paul W. Brandt-Rauf

Biomedicines 2023, 11(2), 258; https://doi.org/10.3390/biomedicines11020258 - 18 Jan 2023

Viewed by 2048

Abstract

Any gene therapy for cancer will be predicated upon its selectivity against cancer cells and non-toxicity to normal cells. Therefore, safeguards are needed to prevent its activation in normal cells. We designed a minimal p14^ARF promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14^ARFmin). The modified p14^ARFmin promoter was linked to bicistronic P14 and truncated BID (tBID) genes, which led to synergistic apoptosis via the intrinsic and extrinsic pathways of apoptosis when expressed. The promoter was designed to be preferentially activated by mutant Ras and completely inhibited by wild-type p53 so that only cells with both mutant Ras and mutant p53 would activate the construct. In comparison to most p53 gene therapies, this construct has selective advantages: (1) p53-based gene therapies with a constitutive CMV promoter cannot differentiate between normal cells and cancer cells, and can be toxic to normal cells; (2) our construct does not induce p21^WAF/CIPI in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14^ARFmin-p14-tBID) demonstrates bidirectional control of its promoter, which is completely repressed by wild-type p53 and activated only in cells with both RAS and P53 mutations; and (4) a novel combination of genes (p14 and tBID) can synergistically induce potent intrinsic and extrinsic apoptosis in cancer cells. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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19 pages, 4080 KiB

Open AccessArticle

C-Terminal p53 Palindromic Tetrapeptide Restores Full Apoptotic Function to Mutant p53 Cancer Cells In Vitro and In Vivo

by Robert L. Fine, Yuehua Mao, Richard Dinnen, Ramon V. Rosal, Anthony Raffo, Uri Hochfeld, Patrick Senatus, Jeffrey N. Bruce, Gwen Nichols, Hsin Wang, Yongliang Li and Paul W. Brandt-Rauf

Biomedicines 2023, 11(1), 137; https://doi.org/10.3390/biomedicines11010137 - 5 Jan 2023

Cited by 1 | Viewed by 1624

Abstract

We previously demonstrated that a synthetic monomer peptide derived from the C-terminus of p53 (aa 361–382) induced preferential apoptosis in mutant p53 malignant cells, but not normal cells. The major problem with the peptide was its short half-life (half-life < 10 min.) due to a random coil topology found in 3D proton NMR spectroscopy studies. To induce secondary/tertiary structures to produce more stability, we developed a peptide modelled after the tetrameric structure of p53 essential for activation of target genes. Starting with the above monomer peptide (aa 361–382), we added the nuclear localization sequence of p53 (aa 353–360) and the end of the C-terminal sequence (aa 383–393), resulting in a monomer spanning aa 353–393. Four monomers were linked by glycine to maximize flexibility and in a palindromic order that mimics p53 tetramer formation with four orthogonal alpha helices, which is required for p53 transactivation of target genes. This is now known as the 4 repeat-palindromic-p53 peptide or (4R-Pal-p53p). We explored two methods for testing the activity of the palindromic tetrapeptide: (1) exogenous peptide with a truncated antennapedia carrier (Ant) and (2) a doxycycline (Dox) inducer for endogenous expression. The exogenous peptide, 4R-Pal-p53p-Ant, contained a His tag at the N-terminal and a truncated 17aa Ant at the C-terminal. Exposure of human breast cancer MB-468 cells and human skin squamous cell cancer cells (both with mutant p53, 273 Arg->His) with purified peptide at 7 µM and 15 µM produced 52% and 75%, cell death, respectively. Comparatively, the monomeric p53 C-terminal peptide-Ant (aa 361–382, termed p53p-Ant), at 15 µM and 30 µM induced 15% and 24% cell death, respectively. Compared to the p53p-Ant, the exogenous 4R-pal-p53p-Ant was over five-fold more potent for inducing apoptosis at an equimolar concentration (15 µM). Endogenous 4R-Pal-p53p expression (without Ant), induced by Dox, resulted in 43% cell death in an engineered MB468 breast cancer stable cell line, while endogenous p53 C-terminal monomeric peptide expression produced no cell death due to rapid peptide degradation. The mechanism of apoptosis from 4R-Pal-p53p involved the extrinsic and intrinsic pathways (FAS, caspase-8, Bax, PUMA) for apoptosis, as well as increasing reactive oxygen species (ROS). All three death pathways were induced from transcriptional/translational activation of pro-apoptotic genes. Additionally, mRNA of p53 target genes (Bax and Fas) increased 14-fold and 18-fold, respectively, implying that the 4R-Pal-p53p restored full apoptotic potential to mutant p53. Monomeric p53p only increased Fas expression without a transcriptional or translational increase in Fas, and other genes and human marrow stem cell studies revealed no toxicity to normal stem cells for granulocytes, erythrocytes, monocytes, and macrophages (CFU-GEMM). Additionally, the peptide specifically targeted pre-malignant and malignant cells with mutant p53 and was not toxic to normal cells with basal levels of WT p53. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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13 pages, 2760 KiB

Open AccessArticle

c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway

by Maria Anele Romeo, Maria Saveria Gilardini Montani, Andrea Arena, Rossella Benedetti, Gabriella D’Orazi and Mara Cirone

Biomedicines 2022, 10(10), 2489; https://doi.org/10.3390/biomedicines10102489 - 5 Oct 2022

Cited by 1 | Viewed by 1558

Abstract

It has been shown that wild-type (wt)p53 inhibits oncogene c-Myc while mutant (mut)p53 may transactivate it, with an opposite behavior that frequently occurs in the crosstalk of wt or mutp53 with molecules/pathways promoting carcinogenesis. Even if it has been reported that mutp53 sustains c-Myc, whether c-Myc could in turn influence mutp53 expression remains to be investigated. In this study, we found that pharmacological or genetic inhibition of c-Myc downregulated mutp53, impaired cell survival and increased DNA damage in pancreatic cancer cells. At the molecular level, we observed that c-Myc inhibition reduced the expression of mevalonate kinase (MVK), a molecule belonging to the mevalonate pathway that—according to previous findings—can control mutp53 stability, and thus contributes to cancer cell survival. In conclusion, this study unveils another criminal alliance between oncogenes, such as c-Myc and mutp53, that plays a key role in oncogenesis. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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17 pages, 3054 KiB

Open AccessArticle

PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis

by Ehsan Sarafraz-Yazdi, Stephen Mumin, Diana Cheung, Daniel Fridman, Brian Lin, Lawrence Wong, Ramon Rosal, Rebecca Rudolph, Matthew Frenkel, Anusha Thadi, William F. Morano, Wilbur B. Bowne, Matthew R. Pincus and Josef Michl

Biomedicines 2022, 10(5), 945; https://doi.org/10.3390/biomedicines10050945 - 20 Apr 2022

Cited by 6 | Viewed by 3270

Abstract

PNC-27, a 32-residue peptide that contains an HDM-2 binding domain and a cell-penetrating peptide (CPP) leader sequence kills cancer, but not normal, cells by binding to HDM-2 associated with the plasma membrane and induces the formation of pores causing tumor cell lysis and necrosis. Conformational energy calculations on the structure of PNC-27 bound to HDM-2 suggest that 1:1 complexes form between PNC-27 and HDM-2 with the leader sequence pointing away from the complex. Immuno-scanning electron microscopy was carried out with cancer cells treated with PNC-27 and decorated with an anti-PNC-27 antibody coupled to 6 nm gold particles and an anti-HDM-2 antibody linked to 15 nm gold particles. We found multiple 6 nm- and 15 nm-labeled gold particles in approximately 1:1 ratios in layered ring-shaped structures in the pores near the cell surface suggesting that these complexes are important to the pore structure. No pores formed in the control, PNC-27-treated untransformed fibroblasts. Based on the theoretical and immuno-EM studies, we propose that the pores are lined by PNC-27 bound to HDM-2 at the membrane surface with the PNC-27 leader sequence lining the pores or by PNC-27 bound to HDM-2. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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Review

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23 pages, 4472 KiB

Open AccessEditor’s ChoiceReview

Endostatin and Cancer Therapy: A Novel Potential Alternative to Anti-VEGF Monoclonal Antibodies

by Gabriel Méndez-Valdés, Francisca Gómez-Hevia, José Lillo-Moya, Tommy González-Fernández, Joaquin Abelli, Antonia Cereceda-Cornejo, Maria Chiara Bragato, Luciano Saso and Ramón Rodrigo

Biomedicines 2023, 11(3), 718; https://doi.org/10.3390/biomedicines11030718 - 27 Feb 2023

Cited by 8 | Viewed by 2730

Abstract

Angiogenesis is a physiological process that consists of the formation of new blood vessels from preexisting ones. Angiogenesis helps in growth, development, and wound healing through the formation of granulation tissue. However, this physiological process has also been linked to tumor growth and metastasis formation. Indeed, angiogenesis has to be considered as a fundamental step to the evolution of benign tumors into malignant neoplasms. The main mediator of angiogenesis is vascular endothelial growth factor (VEGF), which is overexpressed in certain cancers. Thus, there are anti-VEGF monoclonal antibodies, such as bevacizumab, used as anti-cancer therapies. However, bevacizumab has shown adverse events, such as hypertension and proteinuria, which in the most severe cases can lead to cessation of therapy, thus contributing to worsening patients’ prognosis. On the other hand, endostatin is an endogenous protein that strongly inhibits VEGF expression and angiogenesis and shows a better safety profile. Moreover, endostatin has already given promising results on small scale clinical studies. Hence, in this review, we present data supporting the use of endostatin as a replacement for anti-VEGF monoclonal antibodies. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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19 pages, 1002 KiB

Open AccessReview

Recoding of Nonsense Mutation as a Pharmacological Strategy

by Gazmend Temaj, Pelin Telkoparan-Akillilar, Nexhibe Nuhii, Silvia Chichiarelli, Sarmistha Saha and Luciano Saso

Biomedicines 2023, 11(3), 659; https://doi.org/10.3390/biomedicines11030659 - 22 Feb 2023

Viewed by 2830

Abstract

Approximately 11% of genetic human diseases are caused by nonsense mutations that introduce a premature termination codon (PTC) into the coding sequence. The PTC results in the production of a potentially harmful shortened polypeptide and activation of a nonsense-mediated decay (NMD) pathway. The NMD pathway reduces the burden of unproductive protein synthesis by lowering the level of PTC mRNA. There is an endogenous rescue mechanism that produces a full-length protein from a PTC mRNA. Nonsense suppression therapies aim to increase readthrough, suppress NMD, or are a combination of both strategies. Therefore, treatment with translational readthrough-inducing drugs (TRIDs) and NMD inhibitors may increase the effectiveness of PTC suppression. Here we discuss the mechanism of PTC readthrough and the development of novel approaches to PTC suppression. We also discuss the toxicity and bioavailability of therapeutics used to stimulate PTC readthrough. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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24 pages, 2366 KiB

Open AccessReview

Peptides That Block RAS-p21 Protein-Induced Cell Transformation

by Matthew R. Pincus, Bo Lin, Purvi Patel, Elmer Gabutan, Nitzan Zohar and Wilbur B. Bowne

Biomedicines 2023, 11(2), 471; https://doi.org/10.3390/biomedicines11020471 - 6 Feb 2023

Viewed by 2343

Abstract

This is a review of approaches to the design of peptides and small molecules that selectively block the oncogenic RAS-p21 protein in ras-induced cancers. Single amino acid substitutions in this protein, at critical positions such as at Gly 12 and Gln 61, cause the protein to become oncogenic. These mutant proteins cause over 90 percent of pancreatic cancers, 40–50 percent of colon cancers and about one third of non-small cell cancers of the lung (NSCCL). RAS-p21 is a G-protein that becomes activated when it exchanges GDP for GTP. Several promising approaches have been developed that target mutant (oncogenic) RAS-p21 proteins in these different cancers. These approaches comprise: molecular simulations of mutant and wild-type proteins to identify effector domains, for which peptides can be made that selectively inhibit the oncogenic protein that include PNC-1 (ras residues 115–126), PNC-2 (ras residues 96–110) and PNC7 (ras residues 35–47); the use of contiguous RAS-p21 peptide sequences that can block ras signaling; cyclic peptides from large peptide libraries and small molecule libraries that can be identified in high throughput assays that can selectively stabilize inactive forms of RAS-p21; informatic approaches to discover peptides and small molecules that dock to specific domains of RAS-p21 that can block mitogenic signal transduction by oncogenic RAS-p21; and the use of cell-penetrating peptides (CPPs) that are attached to the variable domains of the anti-RAS-p21 inactivating monoclonal antibody, Y13 259, that selectively enters oncogenic RAS-p21-containing cancer cells, causing these cells to undergo apoptosis. Several new anti-oncogenic RAS-p21 agents, i.e., Amgen’s AMG510 and Mirati Therapeutics’ MRTX849, polycyclic aromatic compounds, have recently been FDA-approved and are already being used clinically to treat RAS-p21-induced NSCCL and colorectal carcinomas. These new drugs target the inactive form of RAS-p21 bound to GDP with G12C substitution at the critical Gly 12 residue by binding to a groove bordered by specific domains in this mutant protein into which these compounds insert, resulting in the stabilization of the inactive GDP-bound form of RAS-p21. Other peptides and small molecules have been discovered that block the G12D-RAS-p21 oncogenic protein. These agents can treat specific mutant protein-induced cancers and are excellent examples of personalized medicine. However, many oncogenic RAS-p21-induced tumors are caused by other mutations at positions 12, 13 and 61, requiring other, more general anti-oncogenic agents that are being provided using alternate methods. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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16 pages, 647 KiB

Open AccessReview

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

by Christopher W. Schultz and Avinoam Nevler

Biomedicines 2022, 10(12), 3249; https://doi.org/10.3390/biomedicines10123249 - 14 Dec 2022

Cited by 9 | Viewed by 2864

Abstract

Pyrvinium, a lipophilic cation belonging to the cyanine dye family, has been used in the clinic as a safe and effective anthelminthic for over 70 years. Its structure, similar to some polyaminopyrimidines and mitochondrial-targeting peptoids, has been linked with mitochondrial localization and targeting. Over the past two decades, increasing evidence has emerged showing pyrvinium to be a strong anti-cancer molecule in various human cancers in vitro and in vivo. This efficacy against cancers has been attributed to diverse mechanisms of action, with the weight of evidence supporting the inhibition of mitochondrial function, the WNT pathway, and cancer stem cell renewal. Despite the overwhelming evidence demonstrating the efficacy of pyrvinium for the treatment of human cancers, pyrvinium has not yet been repurposed for the treatment of cancers. This review provides an in-depth analysis of the history of pyrvinium as a therapeutic, the rationale and data supporting its use as an anticancer agent, and the challenges associated with repurposing pyrvinium as an anti-cancer agent. Full article

(This article belongs to the Special Issue Anti-cancer Peptides and Peptide-Like Molecules)

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