The Effect of Telomerase Inhibition on NK Cell Activity in Acute Myeloid Leukemia

Abstract

Purpose: Acute myeloid leukemia (AML) is known to be an invasive and highly lethal hematological malignancy in adults and children. Resistance to the present treatments, including radiotherapy and chemotherapy with their side effects and telomere length shortening are the main cause of the mortality in AML patients. Telomeres sequence which are located at the end of eukaryotic chromosome play pivotal role in genomic stability. Recent studies have shown that apoptosis process is blocked in AML patient by the excessive telomerase activity in cancerous blasts. Therefore, the find of effective ways to prevent disease progression has been considered by the researchers. Natural killer (NK) cells as granular effector cells play a critical role in elimination of abnormal and tumor cells. Given that the cytotoxic function of NK cells is disrupted in the AML patients, we investigated the effect of telomerase inhibitors on NK cell differentiation. Methods: To evaluate telomerase inhibition on NK cell differentiation, the expression of CD105, CD56, CD57, and KIRs was evaluated in CD34+ derived NK cells after incubation of them with BIBR1532. Results: The results showed that the expression of CD105, CD56, CD57, and KIRs receptors reduces after telomerase inhibition. According to these findings, BIBR1532 affected the final differentiation of NK cells. Conclusion: The results revealed that telomerase inhibitor drugs suppress cancer cell progression in a NK cells-independent process.

Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells

“…In this line, tigecycline was used for the activation of NK cells in patients with AML. 14 Liyanage Sd et al reported that human AML is characterized by increased mitochondrial biogenesis and oxidative phosphorylation. 15 According to the similarity in mitochondrial and bacterial ribosomes, it seems that it can also inhibit mitochondrial activity and the oxidative phosphorylation machinery.…”

“…Tigecycline is an FDA‐approved antibiotic; that inhibits mitochondrial protein synthesis required for oxidative phosphorylation. In this line, tigecycline was used for the activation of NK cells in patients with AML 14 . Liyanage Sd et al reported that human AML is characterized by increased mitochondrial biogenesis and oxidative phosphorylation 15 .…”

Regulation of telomerase towards tumor therapy

“…Acute myeloid leukemia (AML) is an aggressive malignancy with highly active telomerase, but some evidence suggests that NK cytotoxicity is impaired in AML patients [ 80 ]. Dizaji Asl K et al proposed a double-edged role of BIBR1532 in cancer cell killing and in negative effect on the NK cell activity [ 81 ]. It may be worthwhile to try to prove that increasing telomerase activity in hematopoietic progenitor stem cells could contribute to an enhanced anti-tumor immune microenvironment.…”