Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)

Abstract

In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34+ bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML.

Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1

“…AML is associated with poor long-term survival, even with newer chemotherapeutic agents. Various studies reported that AML relapse and resistance to chemotherapies may originate from a small clone, known as Leukemic Stem Cells (LSCs) [ 1 ]. LSCs are identified as a chemo-resistant clone that has the ability for limitless self-renewal and also production of a large number of blast cells [ 2 ].…”

Magnetic Nanocarriers Enhance Drug Delivery Selectively to Human Leukemic Cells

“…The main strategy for treatment is using chemotherapy. Although many different clinical antitumor agents are currently used in the treatment of acute promyelocytic leukemia (APL), acute myeloid leukemia (AML), or CML patients, a high proportion of these leukemic patients eventually relapse [31][32][33]. Hence, alternative approaches…”

Recombinant anthrax lethal toxin inhibits cell motility and invasion in breast cancer cells through the dysregulation of Rho GTPases

“…LeTx is a binary toxin composed of two proteins: PA And LF. LF is a zinc-activated metalloprotease that inhibits the MAPK pathway by cleaving MEKs (35,36). Based on the ability of LeTx to cause cell death or inhibition of migration and invasion due to MAPK inhibition, breast cancer cells were treated with LeTx, and the migratory and invasive capabilities of the cells were examined in the present study.…”