Opioids drive breast cancer metastasis through the δ-opioid receptor and oncogenic STAT3

Tripolt, Sabrina; Neubauer, Heidi A.; Knab, Vanessa M.; Elmer, Dominik P.; Aberger, Fritz; Moriggl, Richard; Fux, Daniela

doi:10.1016/j.neo.2020.12.011

Cited by 28 publications

(19 citation statements)

References 49 publications

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“…Tripolt S et al. found that the common analgesic, opioid, triggered breast cancer metastasis via oncogenic JAK1/2-STAT3 signaling to promote epithelial-mesenchymal transition, emphasizing the importance of selective and restricted opioid use ( 39 ). Serum from patients receiving propofol/paravertebral anesthesia for breast cancer surgery inhibited proliferation of MDA-MB-231 cells in vitro , to a greater extent than that from patients receiving sevoflurane/opioid anesthesia-analgesia ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Propofol Inhibits Proliferation and Augments the Anti-Tumor Effect of Doxorubicin and Paclitaxel Partly Through Promoting Ferroptosis in Triple-Negative Breast Cancer Cells

et al. 2022

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BackgroundTriple-negative breast cancer (TNBC) is relatively common in women and is associated with a poor prognosis after surgery and adjuvant chemotherapy. Currently, the mechanism underlying the relationship between propofol and breast cancer is controversial and limited to cell apoptosis. Moreover, there are only a few studies on the effect of propofol on the chemotherapeutic sensitivity of TNBC cells. Therefore, this study explored whether propofol and its commonly used clinical formulations affect the proliferation and chemotherapeutic effects on TNBC cells by regulating cell ferroptosis.MethodsWe selected MDA-MB-231 cells, and the effects of propofol, propofol injectable emulsion (PIE), or fospropofol disodium, alone or combined with doxorubicin or paclitaxel on cell viability, apoptosis, intracellular reactive oxygen species (ROS) accumulation, ferroptosis-related morphological changes, intracellular Fe2+ levels, and the expression and localization of ferroptosis-related proteins were investigated.ResultsWe found that propofol significantly inhibited MDA-MB-231 cell proliferation, and all three propofol formulations augmented the anti-tumor effects of doxorubicin and paclitaxel. The results from the ROS assay, transmission electron microscopy, intracellular Fe2+ assay, western blotting, and multiplex immunohistochemistry revealed that propofol not only induced apoptosis but also triggered ferroptosis-related changes, including morphological changes of mitochondria, increased intracellular ROS levels, and intracellular iron accumulation in MDA-MB-231 cells. The ferroptosis-related p53-SLC7A11-GPX4 pathway was also altered under different treatment propofol, doxorubicin, or paclitaxel regimens.ConclusionPropofol showed anti-proliferation effects on TNBC cells and could be a potential adjuvant to enhance the chemotherapeutic sensitivity of TNBC cells partly by promoting cell ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Propofol Inhibits Proliferation and Augments the Anti-Tumor Effect of Doxorubicin and Paclitaxel Partly Through Promoting Ferroptosis in Triple-Negative Breast Cancer Cells

et al. 2022

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“…Due to the analgesic properties, opioids are widely used during breast cancer surgery. Some laboratory studies showed that opioids inhibit cell-mediated immunity ( 105 ), reduce lymphocyte and macrophage proliferation ( 106 ), and drive breast cancer metastasis ( 107 ). However, the association between opioid-based anesthesia and breast cancer recurrence is inconclusive till now ( 108 ).…”

Section: Randomized Controlled Studiesmentioning

confidence: 99%

Effects of Propofol Versus Sevoflurane on Postoperative Breast Cancer Prognosis: A Narrative Review

et al. 2022

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Perioperative interventions produce substantial biologic perturbations which are associated with the risk of recurrence after cancer surgery. The changes of tumor microenvironment caused by anesthetic drugs received increasing attention. Till now, it’s still unclear whether or not anesthetic drugs may exert positive or negative impact on cancer outcomes after surgery. Breast cancer is the most common tumor and the leading cause of cancer deaths in women. Propofol and sevoflurane are respectively the most commonly used intravenous and inhaled anesthetics. Debates regarding which of the two most commonly used anesthetics may relatively contribute to the recurrence and metastasis vulnerability of breast cancer postoperatively remain. This review aimed to provide a comprehensive view about the effect of propofol versus sevoflurane on the prognosis of breast cancer obtained from pre-clinical studies and clinical studies. Laboratory and animal studies have demonstrated that sevoflurane may enhance the recurrence and metastasis of breast cancer, while propofol is more likely to reduce the activity of breast cancer cells by attenuating the suppression of the immune system, promoting tumor cells apoptosis, and through other direct anti-tumor effects. However, retrospective clinical studies have shown contradictory results about the effects of propofol and sevoflurane on long-term survival in breast cancer patients. Furthermore, recent prospective studies did not identify significant differences between propofol and sevoflurane in breast cancer metastasis and recurrence. Therefore, more preclinical studies and randomized controlled studies are needed to guide the choice of anesthetics for breast cancer patients.

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“…The previous findings were partially corroborated by another group of investigators. 50 Analyses of DOR gene expression performed on clinically available tumor data sets indicated a strong association between increased receptor levels and tumor recurrence/cancer survival. For example, among breast cancer patients, extent of DOR mRNA was directly correlated with disease stage and progression; an accompanying, and consistent, finding was the receptor’s direct relationship with tumor grade.…”

Section: A Judicious Critiquementioning

confidence: 99%

Spoken and Unspoken Matters Regarding the Use of Opioids in Cancer

Rogers¹,

Higa²

2022

JPR

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Pain is among the most debilitating symptoms in patients with cancer. Except for their relatively frequent use during end-of-life care, opioids are often, though not routinely, prescribed during the course of the disease. Whereas the clinical phenomena of tolerance, dependence, and addiction are invariably recognized, the molecular mechanisms which effect these outcomes are not fully understood, even among health care professionals. Also uncertain is the possible unfavorable effect of these agents on cancer progression and survival, an association that may be related to the expression of opioid receptors in some tumors. An intriguing corollary of the latter finding is that cancer cells may also manifest equivalents of the three maladaptive phenomena. Accordingly, instead of re-addressing the societal and epidemiological impact of opioids, this paper has three alternative foci. The first, and most subordinate, focuses on the mu opioid receptor; the second, centers on the unresolved question regarding the potential adverse effect of opioids on tumor growth; the third, and most compelling, concentrates on the cellular apparatus and influences that modulate tolerance, dependence, and addiction in certain cancers exposed to opioids.

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Opioids drive breast cancer metastasis through the δ-opioid receptor and oncogenic STAT3

Cited by 28 publications

References 49 publications

Propofol Inhibits Proliferation and Augments the Anti-Tumor Effect of Doxorubicin and Paclitaxel Partly Through Promoting Ferroptosis in Triple-Negative Breast Cancer Cells

Propofol Inhibits Proliferation and Augments the Anti-Tumor Effect of Doxorubicin and Paclitaxel Partly Through Promoting Ferroptosis in Triple-Negative Breast Cancer Cells

Effects of Propofol Versus Sevoflurane on Postoperative Breast Cancer Prognosis: A Narrative Review

Spoken and Unspoken Matters Regarding the Use of Opioids in Cancer

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