Anticancer α-Helical Peptides and Structure / Function Relationships Underpinning Their Interactions with Tumour Cell Membranes (original) (raw)

Anti-Cancer Peptides: Status and Future Prospects

Molecules

The dramatic rise in cancer incidence, alongside treatment deficiencies, has elevated cancer to the second-leading cause of death globally. The increasing morbidity and mortality of this disease can be traced back to a number of causes, including treatment-related side effects, drug resistance, inadequate curative treatment and tumor relapse. Recently, anti-cancer bioactive peptides (ACPs) have emerged as a potential therapeutic choice within the pharmaceutical arsenal due to their high penetration, specificity and fewer side effects. In this contribution, we present a general overview of the literature concerning the conformational structures, modes of action and membrane interaction mechanisms of ACPs, as well as provide recent examples of their successful employment as targeting ligands in cancer treatment. The use of ACPs as a diagnostic tool is summarized, and their advantages in these applications are highlighted. This review expounds on the main approaches for peptide synthes...

Biomedical Relevance of Novel Anticancer Peptides in the Sensitive Treatment of Cancer

Biomolecules

The global increase in cancer mortality and economic losses necessitates the cautious quest for therapeutic agents with compensatory advantages over conventional therapies. Anticancer peptides (ACPs) are a subset of host defense peptides, also known as antimicrobial peptides, which have emerged as therapeutic and diagnostic candidates due to several compensatory advantages over the non-specificity of the current treatment regimens. This review aimed to highlight the ravaging incidence of cancer, the use of ACPs in cancer treatment with their mechanisms, ACP discovery and delivery methods, and the limitations for their use. This would create awareness for identifying more ACPs with better specificity, accuracy and sensitivity towards the disease. It would also promote their efficacious utilization in biotechnology, medical sciences and molecular biology to ease the severity of the disease and enable the patients living with these conditions to develop an accommodating lifestyle.

A theoretical analysis of secondary structural characteristics of anticancer peptides

Molecular and Cellular Biochemistry, 2010

Here, cluster analysis showed that a database of 158 anticancer peptides formed 21 clusters based on net positive charge, hydrophobicity and amphiphilicity. In general, these clusters showed similar median toxicities (P = 0.176) against eukaryotic cell lines and no single combination of these properties was found optimal for efficacy. The database contained 14 peptides, which showed selectivity for tumour cell lines only (ACP CT ), 123 peptides with general toxicity to eukaryotic cells (ACP GT ) and 21 inactive peptides (ACP I ). Hydrophobic arc size analysis showed that there was no significant difference across the datasets although peptides with wide hydrophobic arcs ([270°) appeared to be associated with decreased toxicity. Extended hydrophobic moment plot analysis predicted that over 50% of ACP CT and ACP GT peptides would be surface active, which led to the suggestion that amphiphilicity is a key driver of the membrane interactions for these peptides but probably plays a role in their efficacy rather than their selectivity. This analysis also predicted that only 14% of ACP CT peptides compared to 45% of ACP GT peptides were candidates for tilted peptide formation, which led to the suggestion that the absence of this structure may support cancer cell selectivity. However, these analyses predicted that ACP I peptides, which possess no anticancer activity, would also form surface active and tilted a-helices, clearly showing that other factors are involved in determining the efficacy and selectivity of ACPs.

Alpha-Helical Cationic Anticancer Peptides: A Promising Candidate for Novel Anticancer Drugs

Cancer has become a serious concern in public health. Harmful side effects and multidrug resistance of traditional chemotherapy have prompted urgent needs for novel anticancer drugs or therapeutic approaches. Anticancer peptides (ACPs) have become promising molecules for novel anticancer agents because of their unique mechanism and several extraordinary properties. Most α-helical ACPs target the cell membrane, and interactions between ACPs and cell membrane components are believed to be the key factor in the selective killing of cancer cells. In this review, we focus on the exploitation of the structure and function of α-helical ACPs, including the distinction between cancer and normal cells, the proposed anticancer mechanisms, and the influence of physicochemical parameters of α-helical ACPs on the biological activities and selectivity against cancer cells. In addition, the design and modification methods to optimize the cell selectivity of α-helical ACPs are considered. Furthermore, the suitability of ACPs as cancer therapeutics is discussed.

On the selectivity and efficacy of defense peptides with respect to cancer cells

Medicinal Research Reviews, 2013

Here, we review potential determinants of the anticancer efficacy of innate immune peptides (ACPs) for cancer cells. These determinants include membrane-based factors, such as receptors, phosphatidylserine, sialic acid residues, and sulfated glycans, and peptide-based factors, such as residue composition, sequence length, net charge, hydrophobic arc size, hydrophobicity, and amphiphilicity. Each of these factors may contribute to the anticancer action of ACPs, but no single factor(s) makes an overriding contribution to their overall selectivity and toxicity. Differences between the anticancer actions of ACPs seem to relate to different levels of interplay between these peptide and membranebased factors.

Peptides with Dual Antimicrobial and Anticancer Activities

Frontiers in Chemistry, 2017

In recent years, the number of people suffering from cancer and multi-resistant infections has increased, such that both diseases are already seen as current and future major causes of death. Moreover, chronic infections are one of the main causes of cancer, due to the instability in the immune system that allows cancer cells to proliferate. Likewise, the physical debility associated with cancer or with anticancer therapy itself often paves the way for opportunistic infections. It is urgent to develop new therapeutic methods, with higher efficiency and lower side effects. Antimicrobial peptides (AMPs) are found in the innate immune system of a wide range of organisms. Identified as the most promising alternative to conventional molecules used nowadays against infections, some of them have been shown to have dual activity, both as antimicrobial and anticancer peptides (ACPs). Highly cationic and amphipathic, they have demonstrated efficacy against both conditions, with the number of nature-driven or synthetically designed peptides increasing year by year. With similar properties, AMPs that can also act as ACPs are viewed as future chemotherapeutic drugs, with the advantage of low propensity to resistance, which started this paradigm in the pharmaceutical market. These peptides have already been described as molecules presenting killing mechanisms at the membrane level, but also acting toward intracellular targets, which increases their success compartively to one-target specific drugs. This review will approach the desirable characteristics of small peptides that demonstrated dual activity against microbial infections and cancer, as well as the peptides engaged in clinical trials.

Peptides with in vitro anti-tumor activity 2014

Two structurally related (48.6% amino acid sequence identity) peptides with cytotoxic activity against human non-small cell lung adenocarcinoma A549 cells were purified from the venom of the Eastern green mamba Dendroaspis angusticeps using reversed phase HPLC. The peptides were identified as members of the threefinger superfamily of snake toxins by mass fingerprinting of tryptic digests. The more potent peptide (LC 50 against A549 cells = 56±4µg/ml) was identical to the previously described toxin C13S1C1 and the less active peptide (LC 50 against A549 cells = 106±5µg/ml) was identical to toxin F-VIII. Toxin C13S1C1 was also cytotoxic against breast adenocarcinoma MDA-MB-231 cells (LC 50 = 62±2µg/ml) and colorectal adenocarcinoma HT-29 cells (LC 50 = 110±4µg/ml). Although the peptide was appreciably less hemolytic activity against human erythrocytes (LC 50 >600µg/ml), it was cytotoxic to human umbilical vein endothelial HUVEC cells (57±3µg/ ml) indicating no differential activity against cell lines derived from neoplastic tissues. Toxin F-VIII was not cytotoxic to MDA-MB-231, HT-29 cells, and HUVEC cells at concentrations up to 300µg/ml and was not hemolytic at concentrations up to 1mg/ml. Neither peptide inhibited growth of reference strains of Escherichia coli or Staphylococcus aureus (MIC values >200µg/ml).

Efficacy of a proapoptotic peptide towards cancer cells

In vivo (Athens, Greece)

Conventional cancer therapies are associated with severe side-effects and the development of drug resistance. Therefore, new strategies to specifically target tumor cells leaving healthy tissue unaffected are of great interest. On this respect, we tested the antimicrobial peptide (KLAKLAK)(2). This peptide exhibits cytotoxicity against human breast cancer and other tumor cells, while healthy cells remain unaffected. Moreover, treatment with this cationic amphipathic peptide results in slower tumor growth and longer overall survival in vivo. Our data suggest a potential use of (KLAKLAK)(2) peptide for patients with breast and other types of cancer.

Antimicrobial Peptides as Anticancer Agents: Functional Properties and Biological Activities

Molecules

Antimicrobial peptides (AMPs), or host defense peptides, are small cationic or amphipathic molecules produced by prokaryotic and eukaryotic organisms that play a key role in the innate immune defense against viruses, bacteria and fungi. AMPs have either antimicrobial or anticancer activities. Indeed, cationic AMPs are able to disrupt microbial cell membranes by interacting with negatively charged phospholipids. Moreover, several peptides are capable to trigger cytotoxicity of human cancer cells by binding to negatively charged phosphatidylserine moieties which are selectively exposed on the outer surface of cancer cell plasma membranes. In addition, some AMPs, such as LTX-315, have shown to induce release of tumor antigens and potent damage associated molecular patterns by causing alterations in the intracellular organelles of cancer cells. Given the recognized medical need of novel anticancer drugs, AMPs could represent a potential source of effective therapeutic agents, either alo...

Molecular mechanisms of anticancer action and cell selectivity of short α-helical peptides

Biomaterials, 2014

Development of functional biomaterials and drugs with good biocompatibility towards host cells but with high potency against cancer cells is a challenging endeavor. By drawing upon the advantageous features of natural antimicrobial peptides and a-helical proteins, we have designed a new class of short a-helical peptides G(IIKK) n I-NH 2 (n ¼ 1e4) with different potency and high selectivity against cancer cells. We show that the peptides with n ¼ 3 and 4 kill cancer cells effectively whilst remaining benign to the host cells at their working concentrations, through mechanistic processes similar to their bactericidal effects. The high cell selectivity could stem from their preferential binding to the outer cell membranes containing negative charges and high fluidity. In addition to rapid membrane-permeabilizing capacities, the peptides can also induce the programmed cell death of cancer cells via both mitochondrial pathway and death receptor pathway, without inducing non-specific immunogenic responses. Importantly, these peptides can also inhibit tumor growth in a mouse xenograft model without eliciting side effects. Whilst this study reveals the clinical potential of these peptides as potent drugs and for other medical and healthcare applications, it also points to the significance of fundamental material research in the future development of highly selective peptide functional materials.