Synergistic antitumor effects of 9.2.27-PE38KDEL and ABT-737 in primary and metastatic brain tumors

Yu, Xin; Dobrikov, Mikhail I.; Keir, Stephen T.; Gromeier, Matthias; Pastan, Ira; Reisfeld, Ralph A.; Bigner, Darell D.; Chandramohan, Vidya

doi:10.1371/journal.pone.0210608

Cited by 14 publications

(13 citation statements)

References 34 publications

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“…Most recently, ABT-737 and two other BH3 mimetics were tested in combination with a chondroitin sulfate proteoglycan 4 (CSPG4)-targeting immunotoxin in patient-derived melanoma, glioblastoma, and breast cancer cell lines and demonstrated significant synergy. The same study further confirmed the efficacy of the combination in in vivo nude mice studies of glioblastoma and metastatic cerebral melanoma [ 45 ].…”

Section: Immunotoxin Processing and Trafficking (Step 2)mentioning

confidence: 64%

Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy

Dieffenbach

Pastan

2020

Biomolecules

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Immunotoxins are a class of targeted cancer therapeutics in which a toxin such as Pseudomonas exotoxin A (PE) is linked to an antibody or cytokine to direct the toxin to a target on cancer cells. While a variety of PE-based immunotoxins have been developed and a few have demonstrated promising clinical and preclinical results, cancer cells frequently have or develop resistance to these immunotoxins. This review presents our current understanding of the mechanism of action of PE-based immunotoxins and discusses cellular mechanisms of resistance that interfere with various steps of the pathway. These steps include binding of the immunotoxin to the target antigen, internalization, intracellular processing and trafficking to reach the cytosol, inhibition of protein synthesis through ADP-ribosylation of elongation factor 2 (EF2), and induction of apoptosis. Combination therapies that increase immunotoxin action and overcome specific mechanisms of resistance are also reviewed.

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Section: Immunotoxin Processing and Trafficking (Step 2)mentioning

confidence: 64%

Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy

Dieffenbach

Pastan

2020

Biomolecules

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“…ABT drugs have been tested on patient glioblastomas in culture [43]; but these molecules are generally considered to be too large to cross the blood-brain barrier (BBB) [44]. Yet, the BBB becomes more porous with age even to such large proteins as albumin [45][46][47].…”

Section: Resultsmentioning

confidence: 99%

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Mehdipour

Skinner

et al. 2020

GeroScience

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Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.

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“…A number of BH3 mimetics have been established, e.g., ABT-737, ABT-263, A-1155463, and S63845, as well as ABT-199 (Venetoclax), which has been approved for treatment of refractory chronic lymphocytic leukemia [38,108,109]. Although BH3 mimetics were less effective in melanoma cells as a single therapy, they revealed synergistic effects in combinations, e.g., with immunotoxins or the proteasome inhibitor bortezomib [42,110]. Due to the in vitro data, one might also expect good combination effects for BH3 mimetics and TRAIL in melanoma cells, as has been previously shown in glioma cells [111].…”

Section: Discussionmentioning

confidence: 99%

Countering TRAIL Resistance in Melanoma

Eberle

2019

Cancers

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Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy. Nevertheless, high mortality has remained, mainly related to tumor heterogeneity and inducible therapy resistance. But the development of new therapeutic strategies and combinations has raised hope of finally defeating this deadly disease. TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy. The principal sensitivity of melanoma cells for TRAIL was demonstrated in previous studies; however, inducible resistance appeared as a major problem. To address this issue, combination strategies were tested, and survival pathway inhibitors were shown to sensitize melanoma cells for TRAIL-induced apoptosis. Finally, cell cycle inhibition was identified as a common principle of TRAIL sensitization in melanoma cells. Mitochondrial apoptosis pathways, pro- and antiapoptotic Bcl-2 proteins as well as the rheostat consisted of Smac (Second mitochondria-derived activator of caspase) and XIAP (X-linked inhibitor of apoptosis protein) appeared to be of particular importance. Furthermore, the role of reactive oxygen species (ROS) was recognized in this setting. Inducible TRAIL resistance in melanoma can be explained by (i) high levels of antiapoptotic Bcl-2 proteins, (ii) high levels of XIAP, and (iii) suppressed Bax activity. These hurdles have to be overcome to enable the use of TRAIL in melanoma therapy. Several strategies appear as particularly promising, including new TRAIL receptor agonists, Smac and BH3 mimetics, as well as selective kinase inhibitors.

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Synergistic antitumor effects of 9.2.27-PE38KDEL and ABT-737 in primary and metastatic brain tumors

Cited by 14 publications

References 34 publications

Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy

Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Countering TRAIL Resistance in Melanoma

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