Somatostatin receptor mediated targeting of acute myeloid leukemia by photodynamic metal complexes for light induced apoptosis

Abstract

Acute myeloid leukemia (AML) is characterized by relapse and treatment resistance in a major fraction of patients, underlining the need of innovative AML targeting therapies. Here we analysed the therapeutic potential of an innovative biohybrid consisting of the tumor-associated peptide somatostatin and the photosensitizer ruthenium in AML cell lines and primary AML patient samples. Selective toxicity was analyzed by using CD34 enriched cord blood cells as control. Treatment of OCI AML3, HL60 and THP1 resulted in a 92, and 99 and 97% decrease in clonogenic growth compared to the controls. Primary AML cells demonstrated a major response with a 74 to 99% reduction in clonogenicity in 5 of 6 patient samples. In contrast, treatment of CD34 + cB cells resulted in substantially less reduction in colony numbers. Subcellular localization assays of RU-SST in OCI-AML3 cells confirmed strong co-localization of RU-SSt in the lysosomes compared to the other cellular organelles. our data demonstrate that conjugation of a Ruthenium complex with somatostatin is efficiently eradicating LSc candidates of patients with AML. this indicates that receptor mediated lysosomal accumulation of photodynamic metal complexes is a highly attractive approach for targeting AML cells. Acute myeloid leukemia (AML) is initiated and propagated by cancer stem cells. Although these leukemic stem cells (LSCs) initially respond to chemotherapy, most patients relapse and die from the disease 1. One explanation is that current therapies only eliminate the tumor bulk which lacks leukemic stem cell properties whereas the LSCs are relatively insensitive. Growing knowledge of the molecular landscape of AML has led to clinical testing of new drugs against driver mutations as well as antibody-based therapies against cell surface proteins with partly disappointing results 2-5. Thus, for the majority of patients there is therapeutic standstill and the urgent need for innovative treatment approaches. Tumor-associated peptides provide attractive characteristics for AML-targeted strategies such as easy availability, convenient purification and storage. In addition, they are less immunogenic, have a high tissue penetration and a high affinity to cellular biomarkers. They provide a rapid clearance from the body and are excellent candidates for straight forward conjugation strategies. It has been shown that somatostatin receptors (SSTR) are expressed on leukemias such as T-cell leukemia and AML 6,7. Using a somatostatin radiobinding assay it was demonstrated that around 12.5% of AML cases express somatostatin receptors 6. Previously, it has been shown that primary AML progenitor cells, characterized by the co-expression of CD34 and CD117 express the somatostatin receptor (SSTR) subtype 2 and that the expression of the SSTR2 receptor was not restricted to the immature CD34 + CD117 + compartment, but also detected on more differentiated AML blasts. Using a transwell migration assay, it was demonstrated that the migration of AML cells towards a gradient

RETRACTED: Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia

“…As a result, the somatostatin biohybrid targets AML cells more effectively. Remarkably, RU-SST is found in lysosomes, suggesting that they are involved in the degradation mechanism [ 187 ]. Another novel strategy, namely non-thermal plasma (NTP), involves an ionized gas made up of excited atoms and molecules.…”

Ruthenium polypyridyl complex-containing bioconjugates

“…Very recently, the same compound was tested in acute myeloid leukaemia (AML) with promising results. [66] The uptake of bioconjugate 29 was finished in 4 h in OA3 cells. Clonogenic assays after incubation with 29 in different leukaemic cell lines revealed reduction of colony growth of 99 %, 98 % and 92 % for OCI-AML3, HL60 and THP1, respectively, after 6 min light exposure and only 25 % in healthy cord blood cells (CB).…”

Lysosomes in acute myeloid leukemia: potential therapeutic targets?

“…Therefore, the biohybrid more specifically targets AML cells. Interestingly, RU-SST localizes within the lysosomes, indicating their involvement in the eradication mechanism [101]. Non-thermal plasma (NTP) is a relatively new addition in the field of cancer therapy.…”