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Abstract and Figures

Opioids are widely administered to alleviate pain, including chronic pain in advanced cancer patients. Among opioids, morphine is one of the most clinically effective drugs for the palliative management of severe pain. In the last few decades, there has been a debate around the possible influence of opioids such as morphine on tumour growth and metastasis. Whilst several in vitro and in vivo studies suggest the possible modulatory effects of morphine on tumour cells, little is known about the impact of this analgesic drug on other mediators such as matrix metalloproteinases (MMPs) that play a key role in the control of cancer cell invasion and metastasis. MMP-9 has been considered as one of the principal mediators in regulation of not only the initial steps of cancer but during the invasion and spreading of cancer cells to distant organs. Herein, current studies regarding the direct and indirect effects of morphine on regulation of MMP-9 production are discussed. In addition, drawing from previous in vivo and in vitro studies on morphine action in regulating MMP-9 production, the potential roles of several underlying factors are summarised, including nuclear factor kappa-B and intracellular molecules such as nitric oxide.
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REVIEW
Opioids and matrix metalloproteinases: the influence of morphine
on MMP-9 production and cancer progression
Samira Khabbazi
1
&Mohammadhossein Hassanshahi
2
&Alireza Hassanshahi
3
&Yaser Peymanfar
2
&Yu-Wen Su
2
&
Cory J. Xian
2
Received: 7 November 2018 /Accepted: 9 January 2019 /Published online: 17 January 2019
#Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Opioids are widely administered to alleviate pain, including chronic pain in advanced cancer patients. Among opioids, morphine
is one of the most clinically effective drugs for the palliative management of severe pain. In the last few decades, there has been a
debate around the possible influence of opioids such as morphine on tumour growth and metastasis. Whilst several in vitro and
in vivo studies suggest the possible modulatory effects of morphine on tumour cells, little is known about the impact of this
analgesic drug on other mediators such as matrix metalloproteinases (MMPs) that play a key role in the control of cancer cell
invasion and metastasis. MMP-9 has been considered as one of the principal mediators in regulation of not only the initial steps of
cancer but during the invasion and spreading of cancer cells to distant organs. Herein, current studies regarding the direct and
indirect effects of morphine on regulation of MMP-9 production are discussed. In addition, drawing from previous in vivo and
in vitro studies on morphine action in regulating MMP-9 production, the potential roles of several underlying factors are
summarised, including nuclear factor kappa-B and intracellular molecules such as nitric oxide.
Keywords Opioids .Matrix metalloproteinases .MMP-9 .Morphine .NF-κB.Nitric oxide
Abbreviations
AC Adenylyl cyclase
AP-1 Activator protein 1
BMM Bonemarrow-derivedmacrophages
CREB cAMP responsive element binding
cAMP Cyclic adenosine monophosphate
cGMP Cyclic guanosine monophosphate
cNOS Constitutive nitric oxide synthase
DRG Dorsal root ganglia
eNOS Endothelial nitric oxide synthase
ECM Extracellular matrix
GPCR G protein-coupled receptor
Gβγ Gbeta-gamma
iNOS Inducible nitric oxide synthase
IL-1βInterleukin 1 beta
IL-4 Interleukin 4
IL-6 Interleukin 6
IκB Nuclear factor-κB inhibitor
LPS Lipopolysaccharide
MMPs Matrix metalloproteinases
MMP-9 Matrix metalloproteinase 9
NF-κB Nuclear factor kappa B
NO Nitric oxide
NOS Nitric oxide synthase
nNOS Neuronal nitric oxide synthase
PKCδProtein kinase C-delta
PKA Protein kinase A
PLC Phospholipase C
PKC Protein kinase C
PI3K Phosphoinositide 3-kinase
PKB Protein kinase B
PEA3 Polyoma enhancer activator 3
Samira Khabbazi and Mohammadhossein Hassanshahi contributed
equally to this work.
*Cory J. Xian
cory.xian@unisa.edu.au
1
School of Medical Science, The South Australian Health and
Medical Research Institute, The University of Adelaide,
Adelaide, SA 5001, Australia
2
School of Pharmacy and Medical Sciences, and University of South
Australia Cancer Research Institute, University of South Australia,
GPO Box 2471, Adelaide SA 5001, Australia
3
Department of Genetics, Faculty of Basic Sciences, Islamic Azad
University, Shahrekord, Iran
Naunyn-Schmiedeberg's Archives of Pharmacology (2019) 392:123133
https://doi.org/10.1007/s00210-019-01613-6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Thus, direct cytotoxic effects of local and systemic anesthetic agents such as lidocaine, ropivacaine, and propofol have been described suggesting anticancer effects (5,6). However, morphine reportedly activates matrix metalloproteinases that then would promote the dissemination of tumors (7). Moreover, perioperative immunomodulatory factors such as undernutrition, anemia, neoadjuvant chemotherapy, as well as the concomitant use of mechanistically distinct anesthetic agents during oncosurgery, render the translation of partially promising preclinical results into clinical practice difficult. ...
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