The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

Biberacher, Viola; Decker, Thomas; Oelsner, Madlen; Wagner, Michaela; Bogner, Christian; Schmidt, Burkhardt; Kreitman, Robert J.; Peschel, Christian; Pastan, Ira; Büschenfelde, Christian Meyer zum; Ringshausen, Ingo

doi:10.3324/haematol.2011.049155

Cited by 41 publications

(32 citation statements)

References 36 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since PKCs are considered to be the putative kinases for KRAS Ser181 phosphorylation (13,20,21), we tested whether treatment with two general PKC inhibitors that are clinically relevant (Bryostatin-1 and Edelfosine; refs. [22][23][24][25][26] were able to revert tumor growth in a dephosphorylation-dependent manner.…”

Section: Pkc Inhibitors Diminish Oncogenic Kras-mediated Tumor Growthmentioning

confidence: 99%

Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

et al. 2014

View full text Add to dashboard Cite

KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors. Cancer Res; 74(4);

show abstract

Section: Pkc Inhibitors Diminish Oncogenic Kras-mediated Tumor Growthmentioning

confidence: 99%

Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

et al. 2014

View full text Add to dashboard Cite

show abstract

“…No unspecific effects of the IT or the Mock-ETA′ could be demonstrated by using the control cell line U937 and a version of Pseudomonas exotoxin A known as PE38. This has been combined with the macrolide lactone bryostatin 1 for the treatment of low-grade and high-grade B cell lymphoma, with a more potent effect than each agent alone (Biberacher et al 2012). Wei et al (2000) demonstrated that pre-treatment with a radioimmunoconjugate improved the effect of an IT in vivo against human B-cell lymphoma.…”

Section: Discussionmentioning

confidence: 98%

In vitro effects and ex vivo binding of an EGFR-specific immunotoxin on rhabdomyosarcoma cells

Niesen

Brehm

Stein

et al. 2014

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

“…Current effort is directed at better understanding the complex regulation machinery at different stages of the pathway by which immunotoxins kill cells. This knowledge may be helpful to enhance the killing effect of these immunotoxins, or even to expand them to the treatment of different malignancies [47,48].…”

Section: Brief Historical Overview Of Pe-based Itsmentioning

confidence: 99%

“…Additionally to CLL cells, the authors showed that BL22 and bryostatin 1 combined treatment exerts a strong apoptotic effect in large B-cell lymphomas and mantle cell lymphoma cells. The authors concluded that this drug synergism should be tested in vivo to evaluate if it can be a feasible therapeutic approach for CLL and B-cell malignancies [48].…”

Section: Insufficient Potency and Combining Therapies To Enhance Potencymentioning

confidence: 99%

Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins

Benhar

2015

Resistance to Targeted Anti-Cancer Therapeutics

View full text Add to dashboard Cite

Immunotoxins are therapeutic molecules that belong to a class of biopharmaceuticals called "Armed antibodies". Immunotoxins are based on very potent toxins of bacterial or plant origin that lack target-cell specificity. To make them target-cell-specific, the non-specific cell binding domains of the original toxins are replaced with a target-cell-specific binding protein, in most cases a monoclonal antibody or a recombinant antibody fragment. The most clinically-advanced immunotoxins are currently being evaluated in phase II and III clinical studies. Like other targeted and non-targeted therapeutics, immunotoxins too suffer from several limitations that may hinder their therapeutic efficacy. Such limitations include, but are not limited to immunogenicity, modification of the extracellular target to which the targeting antibody binds, modification of the intracellular target upon which the toxin acts to cause cell growth inhibition, and insufficient potency as single agents and off-target toxicity, where non-target cells and organs are affected by the immunotoxin, severely impairing its therapeutic index. This chapter is devoted to a group of immunotoxins in which the toxic moiety is derived from exotoxin A (PE) of the bacterium Pseudomonas aeruginosa. The limitations to the efficacy of PE-based immunotoxins, as well as potential solutions for overcoming such limitations, will be presented. Chapter 2 of this book: "Resistance of tumor cells against antibodytargeted protein toxins" by Ulrich Brinkmann et al. is focused on factors that influence the sensitivity or potential resistances of cancer cells towards recombinant immunotoxins which carry truncated and/or mutated derivatives of Pseudomonas exotoxin as cytotoxic payloads.

show abstract

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

Cited by 41 publications

References 36 publications

Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth

In vitro effects and ex vivo binding of an EGFR-specific immunotoxin on rhabdomyosarcoma cells

Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins

Contact Info

Product

Resources

About