Therapeutic peptides for cancer therapy. Part II - Cell cycle inhibitory peptides and apoptosis-inducing peptides

The University of Mississippi Medical Center, Department of Biochemistry, Jackson, 39216, USA.
Expert Opinion on Drug Delivery (Impact Factor: 4.84). 10/2009; 6(10):1049-64. DOI: 10.1517/17425240903158909
Source: PubMed


Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration.
The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that arrest the cell cycle by mimicking CDK inhibitors or induce apoptosis directly are discussed.
The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery.
Inhibition of cancer cell proliferation directly using peptides that arrest the cell cycle or induce apoptosis is a promising strategy. Peptides can be designed that interact very specifically with cyclins and/or cyclin-dependent kinases and with members of apoptotic cascades. Use of these peptides is not limited by their design, as a rational approach to peptide design is much less challenging than the design of small molecule inhibitors of specific protein-protein interactions. However, the limitations of peptide therapy lie in the poor pharmacokinetic properties of these large, often charged molecules. Therefore, overcoming the drug delivery hurdles could open the door for effective peptide therapy, thus making an entirely new class of molecules useful as anticancer drugs.

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Available from: Gene L Bidwell, Feb 22, 2015
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    • "ELP is made of repeated units of a VPGxG pentapeptide motif, where x can be any amino acid except proline (Dan W. Urry et al., 1991). Because it is genetically encoded, the sequence of ELP is easily manipulated to change the repeat length and resulting molecule size, and the sequence can be modified to incorporate targeting peptides, reactive sites for drug attachment, or therapeutic peptides and proteins (Bidwell and Raucher, 2009; Raucher et al., 2009). ELP has previously been used for delivery of small molecule chemotherapeutics (Bidwell et al., 2007; Dreher et al., 2003; MacKay et al., 2009; Moktan et al., 2012, 2010), peptidebased therapeutics (Bidwell and Raucher, 2010, 2005; Bidwell et al., 2013, 2012, 2010; Massodi et al., 2010, 2009b, 2005), and even protein cargo (Shamji et al., 2008a, 2008b, 2007). "
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    ABSTRACT: Abstract Background: Pregnant females are largely overlooked in drug development due to concerns for fetal health. Additionally, pregnancy is often an exclusion criterion in clinical trials, so the safety of many drugs during pregnancy is unknown. Purpose: The goal of this study was to evaluate Elastin-like Polypeptide (ELP), a synthetic protein derived from human elastin, for maternally sequestered drug delivery. ELP is a versatile drug carrier with a long plasma half-life, low immunogenicity, and the ability to be fused to nearly any small molecule or protein-based therapeutic. Methods: We determined the pharmacokinetics, biodistribution, and fetal exposure to the ELP drug carrier using quantitative fluorescence techniques in a rat pregnancy model. Results: After either bolus IV administration or continuous infusion over five days, ELPs accumulated strongly in the kidneys, liver, and placenta, but importantly, little to no ELPs were detectable in the fetus. Within the placenta, ELPs were localized to the chorionic plate and broadly distributed within the labyrinth, but were excluded from the fetal portion of the chorionic villi. Conclusion: These data indicate that ELP does not cross the placenta, and they suggest that this adaptable drug delivery system is a promising platform for prevention of fetal drug exposure.
    Full-text · Article · Aug 2014 · Journal of Drug Targeting
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    • "The therapeutic peptides may through different mechanisms undergo the anticancer effects dependent on their characteristics. Some peptides interact very specifically with cyclins and/or cyclin-dependent kinases or with members of apoptotic cascades [30]–[31]. Recent studies have shown that the peptides can impair the specific signaling pathways and subsequently inhibited the tumor growth or metastasis [8]–[9], [32]. In our study, the antiovarian cancer of PGPIPN was mainly through the induction of apoptosis mediated by down-regulation of BCL2 (Figure 5). "
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    ABSTRACT: Bioactive peptides, either derived from nature resources or synthesized by rational design, have been demonstrated potential for therapeutic agents against numerous human diseases, including cancer. However, the mechanism of therapeutic peptides against cancer has not been well elucidated. Here we show that PGPIPN, a hexapeptide derived from bovine β-casein, inhibited the proliferation of human ovarian cancer cells line SKOV3 as well as the primary ovarian cancer cells in vitro. Consistently, PGPIPIN also decreased tumor growth rate in xenograft ovarian cancer model mice in a dose-dependent manner. Further study demonstrated that the anti-tumor effect of PGPIPN is partially through promoting cell apoptosis by inhibiting BCL2 pathway. Thus, our study suggests that PGPIPN is a potential therapeutic agent for the treatment of ovarian cancer or other types of cancer.
    Preview · Article · Apr 2013 · PLoS ONE
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    • "Therapeutic peptides (TPs) are capable of modulating important protein/protein interactions and eliciting a therapeutic response. There are many examples of TPs targeted to known oncogenes [4], [5], and, if used in the right context in which the TP is matched to a tumor-specific oncogenic lesion, TPs have great promise as targeted and personalized agents. The advantages of TPs lie in their ease of design for any target protein and in their specificity for that target. "
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    ABSTRACT: Treatment of glioblastoma is complicated by the tumors' high resistance to chemotherapy, poor penetration of drugs across the blood brain barrier, and damaging effects of chemotherapy and radiation to normal neural tissue. To overcome these limitations, a thermally responsive polypeptide was developed for targeted delivery of therapeutic peptides to brain tumors using focused hyperthermia. The peptide carrier is based on elastin-like polypeptide (ELP), which is a thermally responsive biopolymer that forms aggregates above a characteristic transition temperature. ELP was modified with cell penetrating peptides (CPPs) to enhance delivery to brain tumors and mediate uptake across the tumor cells' plasma membranes and with a peptide inhibitor of c-Myc (H1). In rats with intracerebral gliomas, brain tumor targeting of ELP following systemic administration was enhanced up to 5-fold by the use of CPPs. When the lead CPP-ELP-fused c-Myc inhibitor was combined with focused hyperthermia of the tumors, an additional 3 fold increase in tumor polypeptide levels was observed, and 80% reduction in tumor volume, delayed onset of tumor-associated neurological deficits, and at least doubled median survival time including complete regression in 80% of animals was achieved. This work demonstrates that a c-Myc inhibitory peptide can be effectively delivered to brain tumors.
    Full-text · Article · Jan 2013 · PLoS ONE
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