Effects of local anesthetics on breast cancer cell viability and migration

Abstract

BackgroundBreast cancer accounts for nearly a quarter of all cancers in women worldwide, and more than 90% of women diagnosed with breast cancer undergo mastectomy or breast-conserving surgery. Retrospective clinical studies have suggested that use of regional anesthesia leads to improved patient outcomes. Laboratory studies have reported that breast cancer cells are inhibited by some local anesthetics at millimolar concentration. Here, we present a comprehensive analysis of the effects of six common local anesthetics on two human breast cancer cell lines. We used concentrations ranging from those corresponding to plasma levels during regional block by local anesthetic (plasma concentration) to those corresponding to direct infiltration of local anesthetic.MethodsHuman breast cancer cell lines, MDA-MB-231 and MCF7, were incubated with each of six local anesthetics (lidocaine, mepivacaine, ropivacaine, bupivacaine, levobupivacaine, and chloroprocaine) (10 μM ~ 10 mM) for 6 to 72 h. Assays for cell viability, cytotoxicity, migration, and cell cycle were performed.ResultsHigh concentrations (> 1 mM) of local anesthetics applied to either MDA-MB-231 or MCF7 cells for 48 h significantly inhibited cell viability and induced cytotoxicity. At plasma concentrations (~ 10 μM) for 72 h, none of the local anesthetics affected cell viability or migration in either cell line. However, at 10 × plasma concentrations, 72-h exposure to bupivacaine, levobupivacaine or chloroprocaine inhibited the viability of MDA-MB-231 cells by > 40% (p < 0.001). Levobupivacaine also inhibited the viability of MCF7 cells by 50% (p < 0.001). None of the local anesthetics affected the viability of a non-cancerous breast cell line, MCF10A. MDA-MB-231 cell migration was inhibited by 10 × plasma concentrations of levobupivacaine, ropivacaine or chloroprocaine and MCF7 cell migration was inhibited by mepivacaine and levobupivacaine (p < 0.05). Cell cycle analysis showed that the local anesthetics arrest MDA-MB-231 cells in the S phase at both 1 × and 10 × plasma concentrations.ConclusionsLocal anesthetics at high concentrations significantly inhibited breast cancer cell survival. At 10 × plasma concentrations, the effect of local anesthetics on cancer cell viability and migration depended on the exposure time, specific local anesthetic, specific measurement endpoint and specific cell line.

Differential effects and mechanisms of local anesthetics on esophageal carcinoma cell migration, growth, survival and chemosensitivity

“…The estimated IC50 of anti-migratory effect of bupivacaine, ropivacaine, lidocaine and mepivacaine in esophageal carcinoma cells are~10 μM,~50 μM, > 100 μM and > 100 μM. Plasma concentrations of these four local anesthetics ranged from 2.8 to 10 μM [15]. Our results suggest that bupivacaine is the only local anesthetics among the four, at clinically achievable concentration, to inhibit migration in esophageal carcinoma.…”

“…Amide local anesthetics act on nerve cells through blocking voltage-gate sodium-channels, resulting in the decreased rate of depolarization and repolarization of excitable nerve cell membrane [10]. Substantial preclinical studies suggest that local anesthetics have direct inhibitory effects on the biological activities of cancer cells, including cell proliferation, migration, invasion and survival [11][12][13][14][15]. The mechanisms of the action of the local anesthetics in cancer cells are via targeting multiple signaling or related molecules, and furthermore are sodium-channel-independent [16,17].…”

Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade

“…The mean peak plasma concentrations of local anesthetics following transversus abdominis plane block is between 1 and 3 μM [26]. Similarly, Li et al's work referred 0.02 to 0.1 mM as clinical relevance doses of local anesthetics [27]. The rational of testing concentration of local anesthetics that far exceeds the plasma concentration is because local anesthetics have wide range of uses in clinical practice and their plasma concentrations can vary widely.…”

“…In addition, the surrounding tissues of tumor could be infiltrated with local anesthetic at the concentration range of clinical preparations. For example, the local infiltration concentration of ropivacaine can reach~8 mM [27]. It is interesting to note that ropivacaine and lidocaine are more effective in inhibiting migration and growth than inducing apoptosis, suggesting that their anti-migratory and anti-proliferative effects are more pronounce in melanoma cells.…”

The Role of Transient Receptor Potential Melastatin 7 (TRPM7) in Cell Viability: A Potential Target to Suppress Breast Cancer Cell Cycle

“…The cells were plated in 96-well plates (3-5 × 10 3 /well) for 12 h and were treated as described before [42]. Then, cells were incubated with 20 µL of 5 mg/mL MTT (Abcam, Cambridge, UK) for 2 h and the resulting formazan crystals were dissolved in dimethyl sulfoxide (200 µL).…”