Cytotoxic Conjugates Containing Translational Inhibitory Proteins

Ramakrishnan, Sundaram; Fryxell, Daniel K.; Mohanraj, D.; Olson, Marilyn C.; By, Li

doi:10.1146/annurev.pa.32.040192.003051

Cited by 34 publications

(20 citation statements)

References 72 publications

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“…The fascinating multimodal activities of RIPs have since long time generated interest towards developing antitumor drugs that selectively target tumor cells 10 . A stern resolve in this regard, particularly in the case of type 1 RIPs, are the immunotoxins [11][12][13][14][15] , RIPs conjugated to specific antibodies, which may present promising options for treating various diseases and interestingly against HIV-infected cells 16 . The action mechanism of RIPs have been extremely imperceptible and numerous accounts have been put forth to decipher the same.…”

mentioning

confidence: 99%

Cytological and Subcellular Response of Cells Exposed to the Type-1 RIP Curcin and its Hemocompatibility Analysis

Mohamed

Veeranarayanan

Minegishi

et al. 2014

Sci Rep

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Curcin, a type 1 ribosome inactivating protein (RIP) is investigated here for its cellular competence on six mammalian cell lines. Cells exposed to curcin (100 mg/ml) for 72 h exhibited significant cellular metabolic arrest, with the cancer cell lines being more sensitive. The viability assessment of the cancer cells in a 3D cell culture based assay revealed highly restricted sprouting and proliferation with near to complete dead cell population. Prominent mitochondrial dysfunction, elevated reactive oxygen species levels, nuclear degeneration, structural/mechanical destabilization and suppression of defense mechanisms were imminent with the RIP treated cells. Expression levels of nuclear factor kB (NF-kB), cytoskeletal focal adhesion kinases (FAK) and vinculin were significantly diminished. Vital cellular organelles as nucleus, mitochondria and actin were severely incapacitated on RIP exposure resulting in multimodal apoptosis and necrosis. The ability of curcin to impart comprehensive shutdown of the cells, especially cancer cells, complemented with its hemocompatibility, opens up possibilities of utilizing this ribotoxin as a prospective therapeutic candidate against cancers of diverse origins.

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confidence: 99%

Cytological and Subcellular Response of Cells Exposed to the Type-1 RIP Curcin and its Hemocompatibility Analysis

Mohamed

Veeranarayanan

Minegishi

et al. 2014

Sci Rep

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“…Although extensively investigated, these studies have so far given disappointing results primarily because of undesirable side effects. Much work remains to be done to find possible uses of these ricin conjugates in experimental and clinical medicine (3,4).…”

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confidence: 99%

Characterization of Ricin Heterogeneity by Electrospray Mass Spectrometry, Capillary Electrophoresis, and Resonant Mirror

Despeyroux

Walker

Pearce

et al. 2000

Analytical Biochemistry

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“…This binding has to be followed by an internalization of the IT. After splicing from the MoAb the ricin A must be translocated to the cytosol where it will affect the ribosomal activity resulting in an irreversible inhibition of protein synthesis [5,20,21]. In different B cell lines we investigated which factors contribute most to the cytotoxic activity of CD22-ricin A IT.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Potency of CD22‐Ricin A Depends on Intracellular Routing Rather than on the Number of Internalized Molecules

et al. 1995

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van Horssen PJ, van Oosterhout YJM, de Witte T, Preijers FWMB. Cytotoxic Potency of CD22-Ricin A Depends on Intracellular Routing Rather than on the Number of Internalized Molecules. Scand J Immunol 1995;41:559-65 Cytotoxicity of immunotoxins (ITs) varies considerably depending on factors like the capability of the target antigen to internalize IT molecules, intracellular processing and routing of the IT. We studied factors that may influence cytotoxicity of CD22-ricin A IT to several B cell lines. The antigen density varied from 5.9xlO3 to 6.0xlO4 molecules/cell. The ID 50, determined by protein synthesis inhibition, varied from 2.1xl0-12 to 3 .8 x l0 " n M IT in absence and from 2 .8 x l0 -14 M to 5 .2 x l0 " 12 M IT in presence of the cytotoxicity enhancer N H 4CI (6 mM). In absence as well as in presence of N H 4CI no correlation could be found between antigen density and ID 50. No relation was observed either with the rate of cytotoxicity. Even in cell lines with a low antigen density, such as KM3, protein synthesis was quickly inhibited. In order to investigate whether the cytotoxicity was dependent on the number of internalized molecules the kinetics of internalization and exocytosis of degraded 125I-labelled CD22 molecules were studied. After 24h the number of internalized CD 22 molecules was highest in Ramos (154,500), followed by Daudi (110,300) and KM3 (69,900). However, despite the higher internalization rate of Daudi the rate of cytotoxicity of 10" s M IT was comparable with KM3. N H 4CI did not influence the number of internalized molecules but postponed degradation of CD22. In conclusion, CD22-ricin A is a very potent and fast acting IT even for elimination of target cells that express low numbers of antigen. These results may have implication for treatment of different B cell malignancies with CD22-ricin A.

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Cytotoxic Conjugates Containing Translational Inhibitory Proteins

Cited by 34 publications

References 72 publications

Cytological and Subcellular Response of Cells Exposed to the Type-1 RIP Curcin and its Hemocompatibility Analysis

Cytological and Subcellular Response of Cells Exposed to the Type-1 RIP Curcin and its Hemocompatibility Analysis

Characterization of Ricin Heterogeneity by Electrospray Mass Spectrometry, Capillary Electrophoresis, and Resonant Mirror

Cytotoxic Potency of CD22‐Ricin A Depends on Intracellular Routing Rather than on the Number of Internalized Molecules

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