Multiple Triphenylphosphonium Cations as a Platform for the Delivery of a Pro-Apoptotic Peptide

Kolevzon, Netanel; Kuflik, Uriel; Shmuel, Miriam; Benhamron, Sandrine; Ringel, Israel; Yavin, Eylon

doi:10.1007/s11095-011-0494-6

Cited by 18 publications

(10 citation statements)

References 63 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This effect fosters the accumulation of cationic molecules [17,47,48], hence inducing high selectivity for mitocans holding a (more or less) lipophilic cation such as a rhodamine scaffold. The same effect applies for triphenylphosphonium cations [49][50][51][52][53][54][55][56][57] and to a small extent for quaternary ammonium ions [58][59][60], zwitterionic N-oxides [60,61] and triterpenes substituted with BODIPYs [62][63][64][65][66] or a safirinium moiety [67]. However, the presence of a cationic center is not alone decisive for achieving high cytotoxic effects [60].…”

Section: Resultsmentioning

confidence: 91%

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

et al. 2020

View full text Add to dashboard Cite

The combination of the “correct” triterpenoid, the “correct” spacer and rhodamine B (RhoB) seems to be decisive for the ability of the conjugate to accumulate in mitochondria. So far, several triterpenoid rhodamine B conjugates have been prepared and screened for their cytotoxic activity. To obtain cytotoxic compounds with EC50 values in a low nano-molar range combined with good tumor/non-tumor selectivity, the Rho B unit has to be attached via an amine spacer to the terpenoid skeleton. To avoid spirolactamization, secondary amines have to be used. First results indicate that a homopiperazinyl spacer is superior to a piperazinyl spacer. Hybrids derived from maslinic acid or tormentic acid are superior to those from oleanolic, ursolic, glycyrrhetinic or euscaphic acid. Thus, a tormentic acid-derived RhoB conjugate 32, holding a homopiperazinyl spacer can be regarded, at present, as the most promising candidate for further biological studies.

show abstract

Section: Resultsmentioning

confidence: 91%

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Most studies report that once introduced into a cell, the KLA peptide (like CT20p) localizes to mitochondria 19 . Unlike CT20p, however, the KLA peptide causes depolarization of the mitochondrial membrane and apoptosis under most conditions tested 39,20,40,21 . Interestingly, a dose effect was observed when the KLA peptide was fused to prostate cancer antigen in that low doses caused apoptosis, while high doses led to necrosis 41 .…”

Section: Discussionmentioning

confidence: 85%

Rational Development of a Cytotoxic Peptide To Trigger Cell Death

et al. 2012

View full text Add to dashboard Cite

Defects in the apoptotic machinery can contribute to tumor formation and resistance to treatment, creating a need to identify new agents that kill cancer cells by alternative mechanisms. To this end, we examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminal, alpha-9 helix of Bax, an amphipathic domain with putative membrane binding properties. Like many anti-microbial peptides, CT20p contains clusters of hydrophobic and cationic residues that could enable the peptide to associate with lipid membranes. CT20p caused the release of calcein from mitochondrial-like lipid vesicles without disrupting vesicle integrity and, when expressed as a fusion protein in cells, localized to mitochondria. The amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs) that have the capacity to harbor targeting molecules, dyes or drugs. The resulting CT20p-NPs proved an effective killer of colon and breast cancer cells in vitro and in vivo, using a murine breast cancer tumor model. By introducing CT20p to Bax deficient cells, we demonstrated that the peptide’s lethal activity was independent of endogenous Bax. CT20p also caused an increase in the mitochondrial membrane potential that was followed by plasma membrane rupture and cell death, without the characteristic membrane asymmetry associated with apoptosis. We determined that cell death triggered by the CT20p-NPs was minimally dependent on effector caspases and resistant Bcl-2 over-expression, suggesting that it was independent of the intrinsic apoptotic death pathway. Furthermore, use of CT20p with the apoptosis-inducing drug, cisplatin, resulted in additive toxicity. These results reveal the novel features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies to activate multiple death pathways in cancer cells.

show abstract

“…The addition of 3-triphenylphosphonium cations (TPPs) improved the ability of the KLA peptide to target to mitochondria and induce apoptosis (i.e. 30μM caused 60% mortality of HeLa cells), increasing the biological activity of the peptide [126]. The formation of a pH-responsive nanocomplex consisting of GCS-g-DMA (glycol chitosan graft with 2,3-dimethylmaleic acid) and KLA peptide resulted in release of the KLA peptide in response to increasing acidic pH, and the accumulation of the KLA peptide in murine tumors [127].…”

Section: Cell-penetrating and Tumor-targeting Peptidesmentioning

confidence: 99%

The Use of Therapeutic Peptides to Target and to Kill Cancer Cells

Boohaker¹,

Lee²,

Vishnubhotla³

et al. 2012

CMC

286

219

View full text Add to dashboard Cite

Peptide therapeutics is a promising field for emerging anti-cancer agents. Benefits include the ease and rapid synthesis of peptides and capacity for modifications. An existing and vast knowledge base of protein structure and function can be exploited for novel peptide design. Current research focuses on developing peptides that can (1) serve as tumor targeting moieties and (2) permeabilize membranes with cytotoxic consequences. A survey of recent findings reveals significant trends. Amphiphilic peptides with clusters of hydrophobic and cationic residues are features of anti-microbial peptides that confer the ability to eradicate microbes and show considerable anti-cancer toxicity. Peptides that assemble and form pores can disrupt cell or organelle membranes and cause apoptotic or necrotic death. Cell permeable and tumor-homing peptides can carry biologically active cargo to tumors or tumor vasculature. The challenge lies in developing the clinical application of therapeutic peptides. Improving delivery to tumors, minimizing non-specific toxic effects and discerning pharmacokinetic properties are high among the needs to produce a powerful therapeutic peptide for cancer treatment.

show abstract

Multiple Triphenylphosphonium Cations as a Platform for the Delivery of a Pro-Apoptotic Peptide

Cited by 18 publications

References 63 publications

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

Rational Development of a Cytotoxic Peptide To Trigger Cell Death

The Use of Therapeutic Peptides to Target and to Kill Cancer Cells

Contact Info

Product

Resources

About