Biochemical and Biophysical Research Communications
Morphine activates blast-phase chronic myeloid leukemia cells and alleviates the effects of tyrosine kinase inhibitors
Introduction
Morphine, a main member of the opiate family, plays a key role in anesthetic pre-medication and management of chronic pain associated with cancer growth [1]. It is a phenanthrene opioid receptor agonist, and binds to and activates the μ-opioid receptor in the central nervous system [2]. In current clinical practice, morphine and anticancer drugs are simultaneously given to patients, particularly those with metastatic cancer. The biological activities of morphine in cancer have recently garnered attention as emerging evidence demonstrate that morphine appeared to affect multiple aspects of tumor progression by activating non-classical opioid receptor signaling.
However, the observations on the effects of morphine on tumor growth and angiogenesis seems to be contradictory. For example, morphine has been shown to suppress tumor angiogenesis through suppression of the hypoxia-induced mitochondrial p38 mitogen-activated protein kinase (MAPK) pathway and inhibition of tumor-infiltrating leukocytes migration [3,4]. In contrast, other studies demonstrate that morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling, and promotes breast tumor growth [5,6]. Apart from tumor angiogenesis, the effects of morphine on tumor cells and tumor stem cells are not well understood [[7], [8], [9]]. Better understanding the roles of morphine in cancer cell and cancer stem cells are essential to guide proper clinical use of morphine in cancer patients.
The aim of this study is to investigate whether morphine affects leukemia cells, and study its combinatory effects with standard of care drugs. Chronic myeloid leukemia (CML) is a hematological stem cell malignancy resulting from the transformation by oncogene BCR-ABL [10]. The first-line treatment for CML patients are BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib (1st generation) and dasatinib (2nd generation). Although BCR-ABL TKIs have significantly improved clinical outcome, patients eventually develop to blast phase disease stage. Blast-phase-CML (BP-CML) CD34 + stem/progenitor cells serve as a reservoir for disease relapse [11]. In this study, we used BP-CML cell model to investigate if morphine affects cancer cells at all stages of development (differentiated and stem/progenitor cells), and studied their response to BCR-ABL TKIs. We also analyzed the underlying molecular mechanism of morphine’s action in BP-CML.
Section snippets
Cell culture, patient cells and drugs
K562 and LAMA84 suspension cell lines (KeyGen Biotech Co., Ltd. China) were grown in RPMI supplemented with 10% fetal bovine serum. BP-CML samples were obtained from patients seen at Xiangyang Central Hospital after signing informed consent. BP-CML mononuclear cells were isolated from fresh bone marrow or peripheral blood of using Ficoll separation, and CD34 + cells were isolated from mononuclear cells using EasySep Human CD34 + Positive Selection Kit (Stemcell Technology, USA). Normal bone
Clinically relevant concentrations of morphine promote growth and protects cells from TKIs-induced growth arrest and apoptosis in BP-CML cell lines
To investigate the effects of morphine on BP-CML cell growth and survival, we labeled proliferating cells with BrdU and apoptotic cells with Annexin V after morphine treatment in K562 and LAMA84 cell lines. The range of concentrations from 100 to 400 nM of morphine were used, which were clinically relevant doses [16]. We found that morphine significantly increased proliferation in K562 and LAMA84 cells compared to control (Fig. 1A). Up to two-fold increase on BP-CML cell growth was observed. In
Discussion
As opioids are the cornerstone drugs for treatment of severe pain, morphine is used clinically for chronic pain associated with cancer growth and treatments with few alternative options. Understanding the contribution of morphine to cancer progression is important for the guide of its clinical application in cancer patients, in particular that existing reports conflict [26,27]. In this work, we demonstrate that morphine activates BP-CML differentiated and stem/progenitor cells, and protects
Declaration of competing interest
All authors declare no conflict of interest.
Acknowledgement
This work was supported by a research grant provided by Hubei University of Education (Grant No. 2015166).
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