Oxycodone stimulates normal and malignant hematopoietic progenitors via opioid-receptor-independent-β-catenin activation

https://doi.org/10.1016/j.bbrc.2020.10.031Get rights and content

Highlights

  • Oxycodone activates normal bone marrow and leukemia stem/progenitor cells.

  • Oxycodone alleviates chemotherapy-induced toxicity in leukemia cells.

  • Oxycodone acts on hematopoietic cells via activation of Wnt/β-catenin.

Abstract

Oxycodone is a common type of opioid used for the treatment of moderate to severe pain. Besides its analgesic effects on neuron cells, the effects of oxycodone on other cell types are yet to be elucidated. We previously demonstrated that oxycodone displayed both pro- and anti-cancer effects on bulk cancer cells. This work further investigated the effects of oxycodone on normal and malignant hematopoietic stem cells. Using hematopoietic CD34+ cells isolated from normal bone marrow (NBM) or patients with acute myeloid leukemia (AML), we showed that oxycodone activates hematopoietic cells regardless of cell development stage and malignant status. Oxycodone dose-dependently increases colony formation and self-renewal capacity of NBM and AML stem/progenitor cells, and promotes proliferation of AML bulk cells. NBM stem/progenitor cells are more sensitive to oxycodone than AML counterparts. In addition, oxycodone alleviates chemotherapy drug-induced toxicity in AML stem/progenitor cells. Mechanism studies demonstrate that oxycodone acts on hematopoietic cells in an opioid-receptor-independent manner. Oxycodone did not affect epithelial growth factor receptor (EGFR) signaling neither but stimulated Wnt/β-catenin signaling. Rescue studies via depleting β-catenin using genetic and pharmacological approaches confirmed that β-catenin was required for the activation of hematopoietic cells induced by oxycodone. Our work demonstrates 1) the protective role of oxycodone in malignant hematopoietic cells from chemotherapy; 2) stimulatory effects of oxycodone in normal hematopoietic stem cells; and 3) ability of oxycodone in Wnt signaling activation.

Introduction

The opioids, including morphine, fentanyl, oxycodone and tramadol, are commonly prescribed in patients with malignant and nonmalignant serious illness for pain management due to their highly potent and effective analgesics effects [1]. Opioids act by binding to specific cell opioid receptors which are designated μ, κ and δ and are found predominantly in the central and peripheral nervous system [2]. The presence of opioid receptors on cardiac, vascular, lung, gastrointestinal tract and blood cells have been reported [3,4]. Accumulating evidence suggests that opioids play other biological roles beyond pain control, including modulating angiogenesis during development and tumor malignancy, regulating immune systems and cancer progression [[5], [6], [7], [8]]. Using pre-clinical in vitro and in vivo models, the majority of studies show that morphine and heroin are immunosuppressive and μ-opioid receptor is involved [4]. Although the conclusions are conflicting, morphine has been extensively studied in various cancers among the opioid receptor agonists [[9], [10], [11], [12], [13]].

Compared to morphine, the affinity of oxycodone for the μ-opioid receptor is lower. However, oxycodone activates the κ-opioid receptor and its equivalent analgesic dose is only two-thirds of morphine with less side effects [14,15]. Oxycodone has been shown to inhibit immune functions in rectal cancer patients [6]. Particularly, oxycodone inhibits the production of interleukin-6 by interleukin-2 stimulated peripheral blood mononuclear cells [16]. We previously demonstrated that oxycodone has both pro- and anti-cancer effects depending on the epithelial growth factor receptor level in cancer cells [17]. In this work, we systematically evaluated the effects of oxycodone on adult stem cells. Although some leukemia stem cells are CD34 [18], CD34 is a well-known marker to identify and isolate human hematopoietic stem/progenitor cells for use clinically in bone marrow transplantation [19]. Using CD34+ cells purified from normal bone marrow of healthy donor and patients with acute myeloid leukemia, we found that oxycodone stimulates normal and malignant hematopoietic stem cell biological activities, and alleviates with toxicity-induced by chemotherapy drug, via activating Wnt/β-catenin pathway.

Section snippets

Drugs, compounds, cell lines, primary cells and CD34 isolation

Oxycodone hydrochloride tablet (Sankyo Pharmaceutical Co. Ltd., Japan) was obtained from the Department of Pharmacy, Wuhan Central Hospital. Cytarabine and ICG001 were obtained from Selleckchem. Human AML cell lines MOLM14 and SKNO-1 (Abace-Biology Inc.) were authenticated using STR profiling analysis and were grown in suspension using RPMI-1640 medium (Invitrogen) supplemented with 10% fetal bovine serum and 100 U/ml Penicillin-Streptomycin. Normal bone marrow (NBM) mononuclear cells were

Oxycodone activates NBM stem/progenitor cell activities

The hallmark features of stem/progenitor cells are their abilities to proliferate, differentiate and self-renew [20]. Colony formation assay using HSC-CFU media is designed for the expansion of CD34+ cells and assesses the differential potential of single human hematopoietic progenitor cell to grow in a distinct colony. In addition, serial replating assay is designed to examine the self-renewal capacity of hematopoietic stem cell [21]. We therefore performed colony formation and serial

Discussion

Although oxycodone is known for its action on central nervous system and spinal cord, its potential effects on other types of cells have not yet been fully revealed. Given the fact that plasma life of oxycodone is 3–5 h and stable plasma levels are reached within 24 h [15], we evaluated the effects of oxycodone on blood stem/progenitor cells. We demonstrated that oxycodone stimulates normal as well as malignant blood stem/progenitor cells activities.

We firstly found that oxycodone significantly

Declaration of competing interest

All authors declare no conflict of interest.

Acknowledgement

This work was supported by a research grant provided by Wuhan Medical Research (Grant No. WZ18Z06).

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