Novel FAO Inhibitor Avocatin B Induces Apoptosis of Acute Monocytic Leukemia Cells in Adipocyte Co-Culture System Via ER Stress and ATF4 Activation

• Published in: Blood 2015-12, Vol.126 (23), p.3692-3692
• Main Authors: Tabe, Yoko, Yamamoto, Shinichi, Kikkawa, Mika, Taka, Hikari, Mogushi, Kaoru, Mastushita, Hiromichi, Miida, Takashi, Andreeff, Michael, Spagnuolo, Paul A, Konopleva, Marina
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.3692.3692

Adipocytes are the prevalent stromal cell type in aged adult bone marrows (BM). We previously demonstrated prominent pro-survival role of BM-derived adipocytes for the acute monocytic leukemia (AMoL) cells, a poor-prognosis subtype of AML (Tabe ASH. 2013). A novel anticancer agent avocatin B, an odd-numbered carbon lipid derived from avocado fruit, has been shown to induce leukemia cell death by inhibiting fatty acid oxidation (FAO) via its accumulation in mitochondria (Lee, Cancer Res. 2015). In this study, we investigated the cytotoxic efficacy and molecular mechanisms of avocatin B in AMoL cells co-cultured with BM-derived adipocytes, mimicking the aging BM microenvironment. AMoL cell lines (THP1, MOLM13 and U937) and mesenchymal stem cells (MSC)-derived adipocytes were used for this study. Adipocytes inhibited spontaneous apoptosis in AMoL cells, consistent with our prior observations. Avocatin B successfully induced apoptosis and cell growth inhibition in AMoL cells (IC50s between 15 and 73uM) with G0/G1 cell cycle accumulation. We further observed that avocatin B synergistically enhanced AraC induced apoptosis in AMoL cells cultured alone or co-cultured with adipocytes (Figure 1). To this end, avocatin B synergized with Ara C with combination index value of 0.15. Immunoblot analysis demonstrated that avocatin B inactivated the stress response kinase phospho- (p-) AMPK and p-p38 MAPK in MOLM13 co-cultured with adipocytes but not in AML cells cultured alone. These results indicate that avocatin B disrupted the energy homeostasis under adipocyte co-culture condition. Metabolic profiling using the capillary electrophoresis mass spectrometry (CE-MS) detected alteration of 12 polar metabolites (fold change > 2, P