Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr‐Abl positive leukemic cells

Abstract

Treatment with Abl tyrosine kinase inhibitors (TKI) drastically improves the prognosis of chronic myelogenous leukemia (CML) patients. However, quiescent CML cells are insensitive to TKI and can lead to relapse of the disease. Thus, research is needed to elucidate the properties of these quiescent CML cells, including their microenvironment, in order to effectively target them. Hypoxia is known to be a common feature of solid tumors that contributes to therapeutic resistance. Leukemic cells are also able to survive and proliferate in severely hypoxic environments. The hypoxic conditions in the bone marrow (BM) allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. A previous report showed that Rakicidin A, a natural product produced by the Micromonospora strain, induced hypoxia-selective cytotoxicity in solid tumors. Here, we describe Rakicidin A-induced cell death in hypoxia-adapted (HA)-CML cells with stem cell-like characteristics. Interestingly, apoptosis was induced via caspase-dependent and -independent pathways. In addition, treatment with Rakicidin A in combination with the TKI, imatinib, resulted in synergistic cytotoxicity against HA-CML cells. In conclusion, Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic BM environment. (Cancer Sci 2011; 102: 591-596) I n solid tumors, oxygen supply is frequently insufficient to adequately support rapid cell proliferation and angiogenesis, which leads to the development of hypoxic regions within the tumor.(1,2) These hypoxic regions are associated with altered cell metabolism, changes in cell cycling and increased resistance to cell death stimuli, and are often associated with a poor prognosis in cancer patients.(3-5) Therefore, the development of cytotoxic compounds that are effective in hypoxic conditions might overcome the therapeutic resistance of cancer cells in hypoxic micro environments.Bone marrow (BM) is known to have low levels of oxygen, and it has been suggested that the hematopoietic stem cells in the BM niche are protected from DNA damage induced by reactive oxygen species (ROS).(6,7) Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells caused by the constitutive activation of Bcr-Abl tyrosine kinase.(8) Treatment of CML has been markedly improved by the development of Abl tyrosine kinase inhibitors (TKI), but the complete eradication of CML cells may not be possible with TKI alone because they are largely ineffective against quiescent CML cells. (9)(10)(11)(12) Although it has not yet been confirmed, CML stem cells could reside in the BM niche because they exhibit characteristics similar to normal hematopoietic stem cells. Previously, we found that CML cells engrafted in the BM survived and proliferated in the severely hypoxic environment; furthermore, these hypoxiaadapted leukemic cells acquired a more primitive phenotype. (13) Recentl...

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

“…Rakicidin A displayed a selective cytotoxicity to hypoxic cancer cells approximately 17.5-fold more potent than to normoxic cancer cells [33]. More recently, rakicidin A was found to induce apoptosis in hypoxia-adapted leukemic cells with stem cell-like characteristics [34]. In addition, rakicidin A exhibited synergistic cytotoxicity in combination with imanitib against hypoxia-adapted leukemic cells which are resistant to Abl tyrosine kinase inhibitors.…”

Therapeutic cyclic lipopeptides mining from microbes: latest strides and hurdles

“…Further, it exerted cytotoxicity towards human melanoma A375 cells mediated by plasma membrane permeabilization (Janek et al 2013). Apart from the above mentioned cyclic lipopeptides, there are many other cyclic lipopeptides with potential roles in medical fields which include Bacillus licheniformis-elaborated lichenysin (Nerurkar 2010), Bacillus subtilis SSE4-elaborated subtulene A (Thasana et al 2010), Paenibacillus kobensis M-elaborated mattacin (Martin et al 2003), Paenibacillus tianmuensis-elaborated battacin (Qian et al 2012b), Paenibacillus elgii-elaborated pelgipeptin (Qian et al 2012a), Micromonospora-elaborated rakicidin (Takeuchi et al 2011), Actinoplanes friuliensis HAG 010964-elaborated friulimicin (Schneider et al 2009;Rückert et al 2014), Serratia marcescens-elaborated serrawettin W1 (Thies et al 2014), Pseudomonas corrugata CFBP 5454-elaborated corpeptins (Strano et al 2015), Pseudomonas fluorescens SS101-elaborated massetolide (Song et al 2014) etc. In fact, the list is exhaustive and it reflects the rationale of searching for novel lipopeptides.…”

“…It induced death of chronic myelogenous leukemia cells by caspase-dependent as well as independent pathways. The result predicted that rakicidin A can be used to target the drug-resistant dormant cancer cells in hypoxic milieu (Takeuchi et al 2011). Bacillus amyloliquefaciens strain fiply 3A produced a bacillomycin D, which dose-dependently killed human cancer cell lines such as alveolar adenocarcinoma A549, renal carcinoma A498, and colon adenocarcinoma HCT-15.…”

Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue

“…The natural product rakicidin A ( 1 , Figure A) is a macrocyclic depsipeptide from Micromonospora sp . with selective toxicity towards hypoxic cancer cells and gleevec‐resistant hypoxia‐adapted chronic myelogenous leukemia (CML) cells . The latter is a model system for CML stem cells.…”