Cell Death Sensitization of Leukemia Cells by Opioid Receptor Activation.
Cell death sensitization of leukemia cells by opioid receptor activation.
Oncotarget. 2013 Apr 16;
Friesen C, Roscher M, Hormann I, Fichtner I, Alt A, Hilger RA, Debatin KM, Miltner E
Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein-coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies.
HubMed – Methadone
Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome.
JAMA. 2013 May 1; 309(17): 1821-7
Wachman EM, Hayes MJ, Brown MS, Paul J, Harvey-Wilkes K, Terrin N, Huggins GS, Aranda JV, Davis JM
Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide polymorphisms (SNPs) in the ?-opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o-methyltransferase (COMT) genes are associated with risk for opioid addiction in adults.To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS.Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother-infant dyads were enrolled. Infants were eligible if they were 36 weeks’ gestational age or older and exposed to methadone or buprenorphine in utero . MAIN OUTCOMES AND MEASURES: Primary outcome measure was length of hospital stay, with between-group differences expressed as ? and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications.Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (? = -8.5 days; 95% CI, -14.9 to -2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63-0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (? = -10.8 days; 95% CI, -18.2 to -3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant.Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS.
HubMed – Methadone
Rotating to Oral Methadone in Advanced Cancer Patients: A Case Series.
J Palliat Med. 2013 Apr 30;
Kilonzo I, Twomey F
Abstract Context: Methadone is increasingly being used to treat patients whose pain does not respond well to other opioids. Advantages over morphine sulphate and its alternatives include low cost, lack of active metabolites and efficacy against neuropathic pain. Objectives: To describe our experience with opioid rotation to methadone and compare the morphine to methadone ratios to previously published data; To discuss two commonly used rotation methods – the Edmonton and Morley-Makin methods. Method: We describe two cases with cancer pain successfully switched to methadone. In both cases the dose of the previous opioid was limited by development of opioid toxicity. We used the Morley-Makin conversion method and modified it by reducing the ‘as required’ dose by a third. The initial methadone doses for these cases were lower than predicted doses. Conclusion: In cases where cancer patients fail to respond or develop tolerance to opioids, conversion to methadone is a reasonable approach. Although equianalgesic tables may not always predict final methadone doses, when properly selected can be useful tools for the experienced clinician. A customised and cautious approach is thus advisable when rotating to oral methadone, especially in patients who have experienced opioid toxicity.
HubMed – Methadone
[Evolution of patients treated with methadone in general practice.]
Presse Med. 2013 Apr 26;
Poloméni P, Pachabezian V, Pequart C, Glauzy C, Bouthillon-Heitzmann P
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