1. Academic Validation
  2. An mTORC1/2 dual inhibitor, AZD2014, acts as a lysosomal function activator and enhances gemtuzumab ozogamicin-induced apoptosis in primary human leukemia cells

An mTORC1/2 dual inhibitor, AZD2014, acts as a lysosomal function activator and enhances gemtuzumab ozogamicin-induced apoptosis in primary human leukemia cells

  • Int J Hematol. 2019 Oct;110(4):490-499. doi: 10.1007/s12185-019-02701-2.
Yu Mizutani 1 Aki Inase 1 Yimamu Maimaitili 1 Yoshiharu Miyata 1 Akihito Kitao 1 Hisayuki Matsumoto 2 Koji Kawaguchi 1 Ako Higashime 1 Hideaki Goto 1 Keiji Kurata 1 Kimikazu Yakushijin 1 Hironobu Minami 1 3 Hiroshi Matsuoka 4
Affiliations

Affiliations

  • 1 Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
  • 2 Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
  • 3 Cancer Center, Kobe University Hospital, Kobe, Japan.
  • 4 Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. matsuoh@med.kobe-u.ac.jp.
Abstract

Gemtuzumab ozogamicin (GO), an anti-CD33 antibody linked to calicheamicin via an acid-labile linker, is the first antibody-drug conjugate (ADC). The acidic environment inside lysosomes of target cells is an important intracellular determinant of the cytocidal action of GO, as the linker is hydrolyzed under acidic conditions. However, lysosomal activity in acute myeloid leukemia (AML) blasts in GO therapy has been insufficiently evaluated. It has been suggested that lysosome activity is suppressed in AML due to hyperactivation of the phosphoinositide 3-kinase/Akt pathway. We therefore hypothesized that agents which activate lysosomal function would potentiate the cytotoxicity of GO. Here, we found that a clinically useful mTORC1/2 dual inhibitor, AZD2014, reduced pH in the acidic organelles, including lysosomes, as shown by increased LysoTracker fluorescent intensity, and synergistically enhanced the cytotoxic effect of GO in primary leukemia cells. GO-induced cytotoxicity appeared to be enhanced with the increase in lysosomal activity by AZD2014. These results indicate that AZD2014 activated lysosomal function in primary leukemia cells, which in turn enhanced the cytotoxicity of GO. Enhancement of lysosomal activity may represent a new therapeutic strategy in the treatment of GO and other ADCs, particularly in cases with low lysosomal activity.

Keywords

AZD2014; Acute myeloid leukemia; Gemtuzumab ozogamicin; Lysosomal function; Primary leukemia cells.

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