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Kahalalide F

Kahalalide F is one of a family of novel peptides isolated from the Hawaiian mollusk, Elysia rufescens. It is currently in Phase II trials for hepatocarcinoma.

Kahalalide F (KF) is a novel antitumor drug of marine origin under clinical investigation. KF showed a potent cytotoxic activity against a panel of human prostate and breast cancer cell lines, with IC50 ranging from 0.07 μm (PC3) to 0.28 μm (DU145, LNCaP, SKBR-3, BT474, MCF7). Importantly, nontumor human cells (MCF10A, HUVEC, HMEC-1, IMR90) were 5–40 times less sensitive to the drug (IC50 = 1.6–3.1 μm). KF cytotoxicity did not correlate with the expression level of the multidrug resistance MDR1 and of the tyrosine kinase HER2/NEU, and only slightly by the anti-apoptotic BCL-2 protein. KF action was triggered rapidly by short pulse treatments (15 min caused 50% maximum cytotoxicity). Neither a general caspase inhibitor (Z-VAD-fmk) nor transcription or translation inhibitors (actinomycin D, cycloheximide) blocked KF action. Flow cytometry analysis revealed that KF induced neither cell-cycle arrest nor apoptotic hypodiploid peak. Using mitochondrial (JC-1)- and lysosomal (LysoTracker Green, Acridine Orange)-specific fluorophores, we detected loss of mitochondrial membrane potential and of lysosomal integrity following KF treatment. Confocal laser and electron microscopy revealed that KF-treated cells underwent a series of profound alterations including severe cytoplasmic swelling and vacuolization, dilation and vesiculation of the endoplasmic reticulum, mitochondrial damage, and plasma membrane rupture. In contrast, the cell nucleus showed irregular clumping of chromatin into small, condensed masses, while chromatin disappeared from other nuclear domains, but the nuclear envelope was preserved and no DNA degradation was detected. Together, these data indicate that KF induces cell death via oncosis preferentially in tumor cells. (Source: Suárez Y, González L, Cuadrado A, Berciano M, Lafarga M, Muñoz A. Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol Cancer Ther. 2003 Sep;2(9):863-72. or http://www.ncbi.nlm.nih.gov/pubmed/14555705).

Current developer:    PharmaMar Inc.

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6: Cruz LJ, Luque-Ortega JR, Rivas L, Albericio F. Kahalalide F, an antitumor depsipeptide in clinical trials, and its analogues as effective antileishmanial agents. Mol Pharm. 2009 May-Jun;6(3):813-24. PubMed PMID: 19317431.

7: Martín-Algarra S, Espinosa E, Rubió J, López López JJ, Manzano JL, Carrión LA, Plazaola A, Tanovic A, Paz-Ares L. Phase II study of weekly Kahalalide F in patients with advanced malignant melanoma. Eur J Cancer. 2009 Mar;45(5):732-5. Epub 2009 Jan 29. PubMed PMID: 19186051.

8: Hosta L, Pla-Roca M, Arbiol J, López-Iglesias C, Samitier J, Cruz LJ, Kogan MJ, Albericio F. Conjugation of Kahalalide F with gold nanoparticles to enhance in vitro antitumoral activity. Bioconjug Chem. 2009 Jan;20(1):138-46. PubMed PMID: 19072538.

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12: Jiménez JC, López-Macià A, Gracia C, Varón S, Carrascal M, Caba JM, Royo M, Francesch AM, Cuevas C, Giralt E, Albericio F. Structure-activity relationship of kahalalide F synthetic analogues. J Med Chem. 2008 Aug 28;51(16):4920-31. Epub 2008 Aug 1. PubMed PMID: 18672864.

13: Pardo B, Paz-Ares L, Tabernero J, Ciruelos E, García M, Salazar R, López A, Blanco M, Nieto A, Jimeno J, Izquierdo MA, Trigo JM. Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors. Clin Cancer Res. 2008 Feb 15;14(4):1116-23. PubMed PMID: 18281545.

14: Piggott AM, Karuso P. Rapid identification of a protein binding partner for the marine natural product kahalalide F by using reverse chemical proteomics. Chembiochem. 2008 Mar 3;9(4):524-30. PubMed PMID: 18224648.

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18: Tilvi S, Naik CG. Tandem mass spectrometry of kahalalides: identification of two new cyclic depsipeptides, kahalalide R and S from Elysia grandifolia. J Mass Spectrom. 2007 Jan;42(1):70-80. PubMed PMID: 17149796.

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20: Gracia C, Isidro-Llobet A, Cruz LJ, Acosta GA, Alvarez M, Cuevas C, Giralt E, Albericio F. Convergent approaches for the synthesis of the antitumoral peptide, Kahalalide F. Study of orthogonal protecting groups. J Org Chem. 2006 Sep 15;71(19):7196-204. PubMed PMID: 16958512.

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23: Sewell JM, Mayer I, Langdon SP, Smyth JF, Jodrell DI, Guichard SM. The mechanism of action of Kahalalide F: variable cell permeability in human hepatoma cell lines. Eur J Cancer. 2005 Jul;41(11):1637-44. PubMed PMID: 15953713.

24: Janmaat ML, Rodriguez JA, Jimeno J, Kruyt FA, Giaccone G. Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling. Mol Pharmacol. 2005 Aug;68(2):502-10. Epub 2005 May 20. PubMed PMID: 15908515.

25: Rademaker-Lakhai JM, Horenblas S, Meinhardt W, Stokvis E, de Reijke TM, Jimeno JM, Lopez-Lazaro L, Lopez Martin JA, Beijnen JH, Schellens JH. Phase I clinical and pharmacokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer. Clin Cancer Res. 2005 Mar 1;11(5):1854-62. PubMed PMID: 15756010.

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29: Stokvis E, Rosing H, López-Lázaro L, Schellens JH, Beijnen JH. Switching from an analogous to a stable isotopically labeled internal standard for the LC-MS/MS quantitation of the novel anticancer drug Kahalalide F significantly improves assay performance. Biomed Chromatogr. 2004 Jul;18(6):400-2. PubMed PMID: 15273981.

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31: Bonnard I, Manzanares I, Rinehart KL. Stereochemistry of kahalalide F. J Nat Prod. 2003 Nov;66(11):1466-70. PubMed PMID: 14640520.

32: Gómez SG, Bueren JA, Faircloth GT, Jimeno J, Albella B. In vitro toxicity of three new antitumoral drugs (trabectedin, aplidin, and kahalalide F) on hematopoietic progenitors and stem cells. Exp Hematol. 2003 Nov;31(11):1104-11. PubMed PMID: 14585376.

33: Suárez Y, González L, Cuadrado A, Berciano M, Lafarga M, Muñoz A. Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol Cancer Ther. 2003 Sep;2(9):863-72. PubMed PMID: 14555705.

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36: Brown AP, Morrissey RL, Faircloth GT, Levine BS. Preclinical toxicity studies of kahalalide F, a new anticancer agent: single and multiple dosing regimens in the rat. Cancer Chemother Pharmacol. 2002 Oct;50(4):333-40. Epub 2002 Aug 3. PubMed PMID: 12357309.

37: Stokvis E, Rosing H, López-Lázaro L, Rodriguez I, Jimeno JM, Supko JG, Schellens JH, Beijnen JH. Quantitative analysis of the novel depsipeptide anticancer drug Kahalalide F in human plasma by high-performance liquid chromatography under basic conditions coupled to electrospray ionization tandem mass spectrometry. J Mass Spectrom. 2002 Sep;37(9):992-1000. PubMed PMID: 12271442.

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41: Nuijen B, Bouma M, Talsma H, Manada C, Jimeno JM, Lopez-Lazaro L, Bult A, Beijnen JH. Development of a lyophilized parenteral pharmaceutical formulation of the investigational polypeptide marine anticancer agent kahalalide F. Drug Dev Ind Pharm. 2001 Sep;27(8):767-80. PubMed PMID: 11699828.

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43: Nuijen B, Bouma M, Manada C, Jimeno JM, Lazaro LL, Bult A, Beijnen JH. Compatibility and stability of the investigational polypeptide marine anticancer agent kahalalide F in infusion devices. Invest New Drugs. 2001;19(4):273-81. PubMed PMID: 11561686.

44: Nuijen B, Bouma M, Manada C, Jimeno JM, Bult A, Beijnen JH. In vitro hemolysis and buffer capacity studies with the novel marine anticancer agent kahalalide F and its reconstitution vehicle cremophor EL/ethanol. PDA J Pharm Sci Technol. 2001 Jul-Aug;55(4):223-9. PubMed PMID: 11505554.

45: Sparidans RW, Stokvis E, Jimeno JM, López-Lázaro L, Schellens JH, Beijnen JH. Chemical and enzymatic stability of a cyclic depsipeptide, the novel, marine-derived, anti-cancer agent kahalalide F. Anticancer Drugs. 2001 Aug;12(7):575-82. PubMed PMID: 11487713.

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