Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of αVβ3-expressing endothelial cells

Abstract

The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed a V b 3 integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DW m ), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia. Within the integrin family, a V b 3 receptors are considered to be an important target for anticancer therapy being upregulated in certain invasive tumors.1 a V b 3 recognizes a specific consensus sequence, an RGD motif, which is present in a number of extracellular matrix proteins like vitronectin, fibronectin, fibrinogen and thrombospondin.2 RGD-containing peptides have been shown to reduce angiogenesis induced by cytokines and to mediate apoptosis in endothelial cells.3 It appears that RGD peptides that are constrained in a cyclic conformation, show an increased affinity for binding to integrins. 4 One example is the cyclic RGD-4C peptide, a potent binder of a 5 b 1 , a V b 3 and a V b 5 used to selectively deliver doxorubicin to tumor blood vessels 5 and to internalize the amphipatic peptide (KLAKLAK) 2 in endothelial cells resulting in cellular apoptosis.

Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells

“…Bax shows a specificity and efficacy for MOM disruption, which is better than that of the cationic peptide (KLAKLAK) 2 , in agreement with the low potency previously reported for this molecule (Borgne-Sanchez et al, 2007;Ellerby et al, 1999). Additionally, the lack of any regulatory capacity in minimal peptide versions with respect to full-length Bax renders these molecules intrinsically and autonomously active, which might be used advantageously as a basis for antitumor therapy.…”

“…However, the mechanisms of cell killing exerted by these antibiotic peptides are unclear, because they appear to include both necrosis, which is secondary to plasma membrane disruption (Papo et al, 2006), and apoptosis, which is induced either by upregulation of death effectors (Chen et al, 2001) or by mitochondrial membrane permeabilization (Ellerby et al, 1999;Law et al, 2006;Mai et al, 2001;Marks et al, 2005;Rege et al, 2007). Of note, the cationic peptide (KLAKLAK) 2 has been reported to have very low potency (Borgne-Sanchez et al, 2007;Ellerby et al, 1999), which precludes its use as an effective anticancer drug.…”

Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

“…HeLa cells were selected for use in the present study due to their low integrin receptor expression levels compared with those of HepG2 cells, which overexpress integrin receptors (30). Fig.…”

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

“…55 However, the cationic peptide (KLAKLAK) 2 has been reported to have a potency that is too low for it to be used as an effective anticancer drug. 41 Because BH3-only proteins either directly or indirectly inhibit prosurvival BCL-2 family members, such as BCL-2, BCL-xL, and MCL-1, to increase cellular sensitivity to anticancer agents, efforts were made to develop so-called BH3 mimetics. 56 Some have entered clinical trials (reviewed in Vogler 57 ).…”