Peptide based therapeutics: new strategy to treatment of therapy resistant cancer.
Cancer is a clonally expanded single founder phenotypic cells resulted due to a various alterations in DNA in form of somatic mutations, epigenetic alterations including their increased ability to repair cross linked DNA. Most of the current chemo therapies based on their effective cross links in DNA structure thereby inducing apoptosis and death of cancer cell [1, 2]. One of the factors that govern chemo therapeutic resistance in tumor cells is enhancement of DNA repair pathways against DNA damaging agents induced cross links . For example, One of the main obstacles over the current chemotherapy to cancer is development of multidrug resistance in advanced and metastatic solid tumors over the commonly used first line anthracycline based [beta]-tubulin sub-units microtubule inhibitors Paclitaxel , and docetaxel . Irrelevant usage of cancer therapeutics has lead to resistance towards systemic cancer therapies which is known to be driven by intra tumoral genetic heterogeneity of tumor cells and genomic instability .
One of the important goals of a successful cancer treatment by chemotherapy is delivery of cytostatic drug to the target tumor cells or tumor environment while leaving normal cells unaffected. However the use of front line chemotherapies is not always successful, progressive usage of chemotherapies often leads to the accumulation of cytostatic drug in target sites were low compared with their accumulation in normal tissues. One possible explanation for this is due the interstitial fluid pressure in solid tumors is higher than the normal tissues which lead to blockage of trans-capillary transport of chemotherapeutic drugs .
Prolonged uses of the single chemotherapeutic agent lead to the development of resistance to multiple structural unrelated compounds known as Multidrug resistance (MDR). A common phenomenon of MDR phenotypic cancer cells is their capability to expel the drugs mediated by ATP-dependent membrane transporter P- glycoproteins (P-gp)  and also decreased drug uptake facilitated by down regulation of copper transporter (CTR1) . MDR appears to be increasing in various types of cancers, for instance treatment of hepatoma with systemic treatment of anti tumor drug doxorubicin (Dox) has led to dropped response rates as little as 10-20% compared to the initial response rates of 70%. In addition to this p-glycoproteins in MDR tumor cells some of these tumor cells have acquired intrinsic ability to expel a broad range of anti cancer drugs and other functional related homologues termed as cross resistance due to the development of glutathione based detoxification [10, 11].
In addition to the alterations of P-gp, deficiency in DNA repair enzymes which participate in DNA repair processes were also known to altered functions in breast cancer drug resistance. For instance reduced expression of an important DNA repair enzyme topoisomerase II genes and loss of DNA-miss match repair activity majorly contributes to the DNA repair from drugs cause double stranded breaks and alkylation damages. Defects in the normal DNA repair process further contributes to the development microsatellite instability, together known as a possible factors associate with development of epipodophyllotoxins resistance in breast cancer cells [12, 13].
Therapeutic inhibition of DNA repair in cancer cells can sensitize the cancer cells towards the chemotherapeutics or else they can function as synthetic lethal approach for treatment of cancers with DNA repair defects such as Nucleotide Excision Repair (NER) of Xeroderma pigmentosum. Hence, there is a significant need for new kind of molecules or therapeutics with low vulnerability to common drug resistance mechanisms for overall increased drug response rates and sustainability.
Based on the recent scientific progress on cellular DNA repair regulations by important DNA replication involved enzymes such as Topoisomerase II, Proliferating Cells Nuclear Antigens (PCNA), Receptor tyrosine kinases of the epidermal growth factor (EGF) receptor family and also DNA damage tolerance mechanisms have paved away to formulate new kind of therapeutic approaches for anti cancer therapy. For instance designing of an inhibitory peptides that can block the protein- protein interactions of important regulatory pathways and components of DNA damage tolerance mechanisms (Translesion synthesis), similarly inhibitory peptides can also be used as ligands to influence the function of target proteins .
Currently, conventional macromolecular chemotherapeutics were replaced with peptides which are selective towards the high affinity intracellular interactions are emerged as an important molecular tool to manipulate important regulatory networks in cancer cells. Present situation of developing a new compounds replaced by the derivatives of old classes by modifying them in their unique ways have entered into current biopharmaceutical industry. It has been estimated that presently it takes an average time span of 8.5 years from being development till approval and clinical phases, and also costs over $559 million in order to reach approved drug to market representing their gaining importance and strict procedures .
Polypeptide antibiotics as therapeutics targets of microbial infection
Innate immunity of the eukaryotic cells responds against pathogens in the form of secreted effectors to defend themselves against microbes, these effectors are presently been considering and evaluating for polypeptide antibiotics. Over a period of time clinicians have used different kinds of polypeptide antibiotics, basically categorized into two different classes namely cyclic decapeptides (loloatins)  and polymyxins . Both these classes of peptides primarily acts by binding to the bacterial cell membrane, thereby altering their structural integrity through increasing water permeability finally leads to the cell death of all gram-negative bacilli except the proteus group. Preliminary investigations by Felius L et., al have shown that antimicrobial cyclic decapeptides not only posess antimicrobial activity but also a promising candidates for cancer therapy. They have exibited anti cancer activity through their effects on apoptosis (poly(ADP-ribose) polymerase (PARP), induction of tumor suppressor and cell signaling proteins (p53 and ERK1/2) of cervical carcinoma cells .
Oncogenes as therapeutic agents
Completion of human genome sequencing and insight over cellular gene expression pathways has significant contributions over identification of wide variety of gene differentially expressed in cancer and normal cells. Among them genetic mutations due to gene deletions or point mutations and epigenetic alterations due to DNA methylation patterns contribute important factors behind the carcinogenesis . Many types of cancer cells have shown to express elevated levels of Interlukin-6 and its expression is more pronounced in human hepatocellular carcinoma. Higher expression of cytokine IL-6 known to activate STAT3 downstream signaling pathways inducing anti apoptotic pathways has been conferred to resistance towards doxorubicin in human liver cancer cells. Yan liu et al., have discovered a small molecular inhibitor named as LLL12 have shown to block the IL-6 induced STAT3 phosphorylation and eventual death of cancer cells by apoptosis, thereby representing its future role in treatment of chemo resistant heap tocellular carcinoma by targeting STAT3 signals. Suggesting that tumor cells require persistence expression of ontogenesis to maintain their transformed phenotype .
DNA repair proteins as therapeutic targets
Every day our cellular DNA is prone to DNA injuries caused by environmental factors and intracellular metabolic products, fortunately our cells have DNA repair machinery that repairs the damages to DNA, cells have repair pathways that include checkpoint controls for proof reading of any such errors by different repair pathways such as Miss Match repair (MMR), Nucleotide Excision repair (NER) and Base Excision Repair (BER). Mutations accumulated over a period of time due to the failure of DNA repair processes leads to the cancer, for instance patients with ataxia-telangiectasia (A-T) does not possess ATM kinase has inability to repair the broken ends caused by UV rays and chemotherapy. Some of these are manifested in case of patients with mutations in BRCA breast cancer genes that lack enzymes in repairing the stalling of replication forks by homologous and Non-homologous end joining. Despite polyploidity of cancer cells, it was found that polyploid cells (cancer cells) often employs a DNA repair programme that normally avoid their dependence on homologous recombination for repair thus attributed towards their uncontrolled cell divisions. Polyploidy cancer cells often express higher level of Mre11 and Rad 50 proteins in order to repair DNA damages quickly than homologous recombination .
The main focus of ongoing cancer research is to know the insights of DNA repair pathway and damage sensing proteins might be translated into formulation of prodiagnosis and better treatment. For therapeutic rationale, it is very important to understand the rate limiting and reversible alterations of DNA repair process for designing more promising drug targets in future (Box 1).
Box 1: Representing newly considered DNA repair mechanisms for anti cancer therapy, excerpts are taken from [23,24] DNA repair process considered for anti cancer therapy Due to the development of intrinsic resistance by cancer cells lias significantly turned down the efficacy of the frontline platinum based anti cancer drugs. Thus targeting of DNA repair mechanisms by peptide based therapeutics were explored recently. Some of the recent advances in inhibition of DNA repair mechanisms. Translesion synthesis of DNA (TLS): TLS is a DNA damage tolerance mechanism approached by cancer cells in order to avoid the bypass the bulky DNA lesions caused by chemotherapeutics. This TLS is mediated by an error prone DNA polymerase including DNA polymerase-^ subunit (REV3L) and TLS scaffolding proteins REVI, recently it. is observed that knocking down the REV3L or REVI gene in mouse model of non small cell lung cancer (NSCLC) have significant contribution towards the increased sensitization of front line Cisplatin therapy. Proliferating cell nuclear antigen (PCNA): Apart from its function as beta clamp loader of replication fork, now it is known that PCNA acts as a adaptor protein for many replication associated DNA repair processes and known to regulate many regulatory proteins associated with cell-cycle progression, checkpoint control and cellular differentiation. Thus, drugs aims at the PCNA interaction with other proteins by its PCNA Interacting Protein (PIP) box and a recently found AlkB-PCNA Interacting Motif (APIM) by Marit et. al., 2009 has now considered for use of APIM peptides for improving cancer chemotherapy.
A Novel approach for use of Peptides as Anti-Cancer Therapeutics
Depending on the knowledge accumulated over the years of research on extensive study of DNA repair pathways and damage response cell signaling, new technologies are being developed in order to further extend the therapeutic application range. Among them designing of specific antagonistic for interacting motifs and specific inhibition of signaling enzymes are some of them. Over 16 years span, around 1111 cancer therapeutics have been entered into clinical study . All cancer therapeutics are designed to interfere with some of the vital functions of cancer cells, the general outcome is typically inhibition of cell proliferation or destruction of tumor cells. These therapeutics are classified into two major categories based on mode of action therapeutics on protein kinases which mainly inhibit one or more specific signaling pathway of cell cycle control or apoptotic pathway and other which interference with DNA replication procedures such as DNA topoisomareases. Conventional peptide therapeutics used previously known to acts as ligands to manipulate function of target protein by its specific extracellular binding, and now they also acts as inhibitory properties for intracellular protein-protein interaction through allosterism .
Some of the targets for using therapeutic peptides act as important molecules, in few model systems they have selected based on their higher affinity intracellular interactions with specific target enzymes or structures and some of them are already used to manipulate important regulatory networks in cancer cells . Peptides which are discovered recently can be used as a mono therapy or in combination with clinical chemotherapeutic agents after discovery of individual peptides that inhibit their target function. Recent discovery of new small peptide, named as iRGD by Ruoslathi, seem to play an additional role of peptides are discovered in mouse known to act not only as therapeutics but also aids in penetration of other chemotherapeutic agents deep into the solid tumors.
Administration of iRGD peptide along with other common existing drugs have reported to significantly increase (From 15% to 80%) the amount of drug reached into a cancer cells. This will not only helps to kill effectively but also reduces drug dose to 1/3 of conventional usage. Since cancer cells are known to expel drugs, and also <10-15% is reached through them named as tumor penetrating peptides, since this peptide has the capability to bind specific [[alpha].sub.V] integrins through a signature motif of arginine-glycine-aspartate, this motif acts as a ligand to neuropilin-1 receptor thereby increases the permeability of vascular tumor cells, this peptide has proven significance results not only towards increasing vascularity but also shown to penetrate when it is conjugated to the nano particles and monoclonal antibodies [28, 29]. As more data linking inhibitors and intracellular cross talk emerges pharmaceutical manipulation and design of new novel peptides would be an advantage. We are still far from being clear to understand how specific peptide ligand bind to their targets efficiently and specifically interfere with signaling functions and reach intracellular target sites without loss of their bioavailability?
Designing of Inhibitory Peptides
The designing of inhibiting peptides from natural binders are based on available high resolution crystallographic data and NMR experiments in order to study the interaction surface between target and its ligand. For instance the protein- protein interaction between matri cellular proteins TSP-1 (Thrombospondin-1) /FGF-2 (fibroblast growth factor) were exploited to design a inhibitory peptide, this kind of designing inhibitory peptides has drawn a considerable interest over few years. TSP-1 participates in inhibition of angiogenesis which is mediated by its interactions with CD36, integrins receptors in endothelial cells . The interaction between TSP-1 with angiogenic factors such as FGF-2 and PDGF might be exploited for designing a therapeutic intervention through their mechanism of angiogenesis regulation. Thus inhibitory peptide might be active in metronomic chemotherapy where frequent administration of lower doses of chemotherapy is proposed to optimize the overall anti angiogenic property of chemotherapeutics . These finding may indicate inhibitory peptide endogenous domains with high affinity can be used without screening of peptide libraries.
The main difference between natural binders and designed inhibitory peptides is not known, Knowledge of the target protein structure or its interface of natural partner is unknown. These peptides were selected based on random sequence identity synthetic peptide library. These random peptide libraries generate inserts with 12-20 amino acids long, thus generating high probability of these specific binders to predetermined targets known as peptide aptamers (PAs). PAs are small and conceptually similar to antibodies and they are isolated by yeast-two hybrid screening of large PAs library that consists of random peptide inserts against a target protein. This selected PAs in yeast cells allow us to identify interactors in mammalian cells. scientists are able to isolate various peptides which inhibits cancer related intracellular proteins involved in cell cycle progression (CDK1), cell signaling (RAS) and viral onco proteins such as HPV16-E6 & E7) by this method [32, 33]. These peptide aptamers have shown excellent anti-tumor effects and also more reliable over pleiotropic effects of current RNA interference techniques existing for cancer treatment, thus opening its wide usefulness in usage as therapeutic agents .
Mode of delivery of Peptide Therapeutics
conventional peptide used so far exert their action on cell surface by inducing or inhibiting one or multiple signal transduction pathways, with the knowledge acquired over a time period have allowed to design peptides that deploy them intracellular as cytosolic or nuclear signaling modulators. In order to perform first peptides need to be internalized.
Peptide Conjugated Liposomes
One of the recognized strategies to improve overall therapeutic effectiveness of existing anti cancer cytostatic drug delivery is encapsulating the drugs into targeting liposomes, which bind to tumor specific cell surface receptors. .
Protein Transduction Domains (PTDs)
Delivery of bioactive peptides across blood brain barrier is restricted to 400- 600 Da. Currently, efficient modes delivery of therapeutic compounds was achieved by fusion of therapeutic peptides with short peptide sequences called PTDs. They have shown to be a promising tool for rapid translocation into nucleus for instance peptides that combines RGD sequence with a peptidic ligand for a transmembrane receptor neuropilin-1 (NRP-1) aids in penetration of drug into tumor .
Challenges for invivo use of Peptide Therapeutics
One of the fundamental problem using therapeutic peptides against cancer is their stability in In vivo conditions against serum and tissue peptidases (proteases). It seems to be retractable to increase resistance of these peptide drugs by modification (acetylation and amidation) of N and C-terminus of the peptides respectively replacement of the amino acids at the predicted cleavage sites with D-amino acids, this mode of designing and modification of peptide have shown to improve stability of a recently discovered glucagon like peptide GLP-1-(7-34)-amide It has been developed as a treatment for Type II diabetes. This peptide has shown to be more stable towards endogenous proteases and increased half life from minutes to two hours while retaining its biological activity. .
[FIGURE 1 OMITTED]
One of the potential problem of using peptide therapeutics is their ability to provoke immunogenicity of host system, as human immune cells have some receptors such as TLRs for sequence specific peptide patterns of foreign peptides this problem has been approached by cyclization of linear peptides by head to tail cyclization linking their N and C-terminus of polypeptide sequence and PEGylation .
Other important problem by use of peptides therapeutics is their bioavailability, due to their smaller molecular masses often renders them to expel from the circulatory system by renal clearance. This problem can overcome by addition of these therapeutic peptides by attaching with polyethylene glycol (PEG) moities by increasing overall molecular mass, for example PEG-Intron and Pegasys, both are used in the treatment of hepatitis C infections have shown to be a good clinical and pharmacokinetic profiles .
Concluding remarks and Future Perspectives
One of the most important challenges of current oncology research is to develop a highly specific anti cancer therapeutics that can discriminate between normal and tumor cells. For instance, recent evidence of use on tumor targeting by use of peptide that combines the RGD sequence with peptidic ligand for a transmembrane receptor neutropilin-1 has not only helped to selective tumor vascular targeting but also facilitates the penetration of drug into tumors. The translational recent data from Rusolathi laboratory suggested that first clinical studies on humans with iRGD are being carried out in laboratory for introducing a new class of peptide therapeutics from a "bench to bedside" .
Some of the short peptides are key players of ligand induced gene expressions and other physiological responses. Currently pharmacological manipulation of the peptides with intracellular transport of chemotherapeutic drugs is a promising option to treat chemotherapy resistant tumors. Moreover, the binding of these peptides with bait proteins of interest might inhibit the complex cross talk of downstream signaling pathways, such as DNA damage sensing and repair proteins, which lead to constant loss of damages response proteins. For better understanding of molecular pharmacological aspects of peptides, together with the information of high throughput screening of peptides by phage systems will soon lead to discovery of a new era of peptide-based therapeutics, including current protein transduction domain (PTD) and integrin binding peptide therapeutics for intracellular targets, which will drive major clinical benefits for cancer patients. Consequently, minimizing the risk for normal cells can provide rational basis of cancer tailored treatments.
The author would like to thank Professor Marit Otterlei for her motivation behind writing this manuscript, DNA repair and stability group, IKM for introducing me to this exciting field of DNA repair, Faculty of Medicine, NTNU, Trondheim, Norway.
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Chandra Sekhar Chirumamilla (1) and Varalakshmi Lalithya Pratti (2)
(1) Department of Cancer and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
(2) Faculty of Bio-Science engineering, Ghent University, Belgium
Table 1: Selected therapeutic peptides currently being developed. Ligand Disease Mechanism of action Lixisenatide Type 2 diabetes Agonist of glucagon-like (ZP10, AVE0010) peptide 1 receptor Danegaptide Arrhythmias A modified dipeptide with a (GAP-134) potent gap junction modifier specifically inhibits the re-entry arrythmia mechanism ZP14801AP214) Ischemia and SIP *-modified peptide binds Inflammation with the melanocortm receptors inhibits inflammation of post surgical organ dysfunction Afamelanotide Orphan disease Synthetic analog of [alpha]-MSH erythropoietic that was shown to induce skin protoporphyria pigmentation through IMA901 Advanced renal This vaccine comprises of 10 vaccine cell carcinoma tumor associated peptides frequently found to be over expressed n renal cell carcinma Ligand Clinical trails Lixisenatide Phase III trails (ZP10, AVE0010) Danegaptide Phase II (GAP-134) ZP14801AP214) Phase II Afamelanotide Approved by EMA IMA901 Phase II vaccine Information was obtained from the http://www.clinicaltrails.gov EMA, European Medicine Agency