Targeting Malignant Mitochondria With Therapeutic Peptides

Abstract

The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondria often rely on disruption of protein-protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion.The mitochondrion holds importance among cellular organelles in consideration of selective anticancer therapy because it is the nexus for propagating malignant transformation and controls cell death. The mitochondrion is a universal target in all cancer cells, and new information about functional and structural differences between healthy and malignant cells continues to emerge [1]. Peptides that specifically target malignant mitochondria offer advantages of low toxicity, high specificity and generally increase the range of interactions that are difficult to target with small molecules (e.g., protein-protein, protein-lipid and protein-DNA) [2]. However, the benefits of peptides are offset by difficulties in delivery, such as degradation by proteases and rapid clearance. As such, the delivery of peptide/ protein therapeutics is almost exclusively by the parenteral route, but the status quo is actively being challenged by broad efforts (e.g., liposomes, microparticles, nanoparticles, 'smart' polymers, hydrogels and chemical modifications to the peptide/protein) to achieve more convenient routes of administration (i.e., oral, nasal and transdermal) and improved pharmacokinetics [3][4][5]. However, peptides, in many cases, are far from passive in the delivery process and through the maze that is drug delivery (from route of administration to perhaps a target residing within a specific organelle), peptides are employed as the vehicle, homing motif and trans-/intra-cellular passport [6].There is an emerging view in cancer therapy that the way in which a cancer cell dies (i.e., immunogenic cell death) is important for a durable response [7]. However, traditional chemo therapy and immune response are in conflict because chemotherapy (e.g., DNA-© 2012 Future Science Ltd * Author for correspondence: Tel.: +1 801 581 7120 Fax: +1 801 585 3614 carol.lim@pharm.utah.edu. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript....

Mitochondrial targeted peptides for cancer therapy

“…1). Thus, VDAC plays an important role in regulating the relationship between mitochondrion and cytosol [18]. Evidences indicate that VDAC activity can be modulated by a variety of proteins, notably members of the Bcl-2 family.…”

“…In vitro Induce caspase-dependent apoptosis, induce MOMP without the participation of Bax and Bak [80] Ant-BH3 Targeted Bcl-x L and lead to MOMP [18] p15tBID…”

“…All of the BH3 proteins (e.g., PUMA, NOXA, Bad, Bim, and Bid) are classified as pro-apoptotic, while Bcl-2 proteins with four regions of high sequence similarity (BH1, BH2, BH3, and BH4) are anti-apoptotic (e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and Bfl1) with the exceptions of Bak and Bax. In stress conditions, BH3-only proteins bind to the BH3 domain of anti-apoptotic Bcl-2 proteins, leading to displacing and releasing of proapoptotic BAK or BAX, followed by pore formation in the mitochondrial outer membrane, and release of pro-apoptotic factors such as Cyt c that leads to caspase activation and commits the cell to death [18,23]. On the other hand, Bcl-2 and Bcl-xL exert their anti-apoptotic activity by diverting Bax and preventing it from forming MOM channels (Fig.…”

“…It is now clear that impaired apoptosis leads to tumor development and metastasis [16]. Cell death is mostly classified into either subtypes of stepwise regulated programmed cell death (apoptosis) or a passive disintegration cell death (necrosis) [17,18], which both are regulated by different but overlapping pathways. The critical mitochondrial event in apoptosis is mitochondrial outer membrane permeabilization (MOMP), which allows release of the pro-apoptotic factors, including cytochrome c (Cyt c) to activate caspases and apoptosisinducing factor (AIF), second mitochondria-derived activator of caspase (Smac), endonucleases, and a serine protease HTRA2 [19].…”

The CT20 peptide: More than a Piece of Bax

“…A major advantage is the potential to design peptides that target specific protein-protein interactions or organelles, like the mitochondria [1,2] . While organelle targeting sequences, such as mitochondrial targeting sequences, are known and characterized, their use is largely restricted to targeting non-peptide cargo rather than as a component of a "peptide drug" [3] . One strategy is to derive peptides from previously characterized, endogenous cellular proteins.…”