No abstract

Our work clearly demonstrates the inhibitory effects of ropivacaine in breast cancer by disrupting mitochondrial function. Our findings provide a proper understanding of how local anesthetics reduce the risk of tumor recurrence, and thus, support the use of ropivacaine for surgery and to control pain in patients with breast cancer.

Background: Retrospective analysis and pre-clinical studies suggest that local anesthetics have anti-tumoral effects. However, the association between cancer recurrence and the use of local anesthesia is inconclusive and most reports are based on single local anesthetic results. Methods: The biological effects (growth, migration and survival) of four common local anesthetics on esophageal carcinoma cells were compared. Biochemical assays on molecules involved in cell migration and proliferation were analyzed. Results: Ropivacaine and bupivacaine significantly inhibited esophageal carcinoma cell migration, at clinically relevant micromolar concentrations. Mepivacaine and lidocaine showed less potent cell migration inhibition than ropivacaine or bupivacaine. All four local anesthetics inhibited cell proliferation. Of note, the effective concentration of anti-proliferative activities requires higher doses. At millimolar concentrations of these local anesthetics, cell apoptosis was moderately affected. Drug combination analysis demonstrated that two of four local anesthetics augmented chemotherapeutic drugs in inhibiting migration. However, all four local anesthetics significantly augmented chemotherapeutic drugs in inhibiting growth and inducing apoptosis. The anti-growth and anti-survival effects of four local anesthetics were attributed to mitochondrial dysfunction and oxidative damage. The anti-migratory effect of local anesthetics is likely through decreasing Rac1 activity. Conclusions: Our work demonstrates the differential effects and proposes the mechanisms of local anesthetics on esophageal carcinoma cell migration, growth, survival and chemosensitivity.

Although substantial evidence shows the link of local anesthesia and decreased tumor recurrence, the role of amide‐linked local anesthetics, particularly bupivacaine, on angiogenesis (a hallmark of tumor progression and metastasis) has not been revealed. In this work, we demonstrate the anti‐angiogenic activity of bupivacaine and its underlying mechanism in endothelial cells. We show that bupivacaine inhibits early stage of capillary network formation via suppressing endothelial cell migration without affecting adhesion to matrix. Bupivacaine also inhibits endothelial cell growth and survival. Mechanism analysis indicates that bupivacaine inhibits mitochondrial respiration via decreasing mitochondrial respiratory activity of complex I and II but not IV or V, resulting in energy depletion, oxidative stress, inhibition of Akt/mTOR, and activation of AMPK pathway. The rescue of an antioxidant NAC on the effects of bupivacaine confirms that bupivacaine inhibits angiogenesis through oxidative stress‐dependent inhibition of Akt/mTOR and activation of AMPK. Our work clearly demonstrates the inhibitory effects of bupivacaine on angiogenesis via targeting mitochondria. Our findings are in line with the previous work providing the preclinical evidence on how local anesthetics could influence the outcome of cancer patients.

Aims: Retrospective clinical studies have shown that opioids could potentially affect the risk of cancer recurrence and metastasis. Better understanding of the effects of opioids on cancer will help to select the optimal anesthetic regimens to achieve better outcomes in cancer patients. Background: Increasing evidence has shown the direct effects of opioids on bulk cancer cells and cancer stem cells. Opioid such as nalbuphine is approved to control cancer-associated pain but little is known on their possible cancer effects. Objective: To assess the biological effects of nalbuphine on acute myeloid leukemia (AML) differentiated and stem/progenitor CD34+ cells. Method: AML CD34+ cells were isolated with colony formation, growth and apoptosis assays performed. Biochemical and immunoblotting analyses were conducted in AML cells exposed to nalbuphine. Result: Nalbuphine at clinically relevant concentrations was active against a panel of AML cell lines with varying IC50. Importantly, nalbuphine augmented the efficacy of cytarabine and daunorubicin in decreasing AML cell viability/growth. Besides bulk AML cells, we noted that nalbuphine was effective and selective in decreasing viability and colony formation of AML CD34+ cells while sparing normal hematopoietic CD34+ cells. The action of nalbuphine on AML cells is not associated with opioid receptors but via inhibiting Ras/Raf/MEK/ERK signaling pathway. Overexpression of constitutively active Ras partially but significantly reversed the inhibitory effects of nalbuphine on AML cells. Conclusion: Our findings reveal the selective anti-AML activity of nalbuphine and its ability in inhibiting Ras signaling. Our work suggests that nalbuphine may be beneficial for leukemia patients.