Table 1.
Summary extracted data from studies examining amino amide local anaesthetics which meet systematic review selection criteria. 5-FU, 5-fluorouracil; 8-OHdG, 8-hydroxy-2' -deoxyguanosine; ABCG2, ATP-binding cassette G2; AKT, protein kinase B; Bax, BCL2-associated X; Bcl-2, B-cell lymphoma 2; c-Met, c-mesenchymal-epithelial transition factor; c-Src, Proto-oncogene tyrosine-protein kinase Src; DDP, diamminedichloroplatinum; EMT, epithelial-to-mesenchymal transition; ERK1/2, extracellular signal-related kinase 1/2; GSK3B, Glycogen synthase kinase-3 beta; IL-6, interleukin-6; mTOR, mammalian target of rapamycin; miR, micro RNA; MLC, myosin light chain; MMP, matrix-metalloproteinase; MRP, multidrug resistance-associated protein; NLC-DTX, nanostructured lipid carrier-docetaxel; PI3K, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; RARβ2, retinoic acid receptor beta 2; RASSF1A, Ras association domain-containing protein 1; ROCK, Rho-associated, coiled-coil containing protein kinase 1; ROS, reactive oxygen species; SCC, squamous cell carcinoma; SIRT, sirtuin 1; SOX4, SRY-related HMG-box 4; TGF, transforming growth factor.
| 1st author and year | Study type | Cancer type (cell line) | Local anaesthetic(s) studied | Local anaesthetic concentration | Chemotherapy agent(s) studied | Interaction observed (e.g. no effect, synergistic effect, additive effect, etc) | Mechanism(s) studied (if any) |
|---|---|---|---|---|---|---|---|
| Li 201451 | In vitro | Breast (MCF-7, MDA-MB-231) | Lidocaine | 10 μM–1 mM | Cisplatin | Lidocaine enhanced the cytotoxic effects of cisplatin | Upregulation of RARβ2 and RASSF1A (promoters of tumour suppressor genes) |
| Xing 201746 | Both | Hepatocellular (HepG2) | Lidocaine | 100 μM–10 mM in vitro, 30 mg kg−1 twice weekly in vivo | Cisplatin | Lidocaine–cisplatin treatment was more cytotoxic in vitro and suppressed tumour growth more effective in vivo than either agent used alone | Bcl-2, Bax, and cleaved caspase-3 activation, activation of ERK1/2, p-38 cascade |
| Yang 201949 | In vitro | Lung cancer (A549/DDP) | Lidocaine | 1–100 μM | Cisplatin | Lidocaine reduced cisplatin resistance | miR-21 expression |
| Liu 202247 | In vitro | Skin squamous cell carcinoma (A431) | Lidocaine | 0–10 mM | Cisplatin | Lidocaine reduces cisplatin resistance | miR-30c/SIRT1 pathway activation |
| Freeman 201844 | In vivo | Breast (4T1 murine) | Lidocaine | 1.5 mg kg−1 bolus then 2 mg kg−1 h−1 infusion | Cisplatin | Enhanced effect in terms of reduced pulmonary metastases, no effect on liver metastases | No significant difference in serum IL-6 noted |
| Zhang 202048 | In vitro | Gastric (MGC-803, MGC-803/DDP) | Lidocaine | 25 μM–200 μM | Cisplatin | Lidocaine reduced cisplatin resistance | Inhibition of miR-10b, AKT/mTOR and β-catenin pathway repression |
| Gao 201845 | Both | Breast (MDA-MB-231, MCF-7) | Lidocaine | In vitro 12 mg kg−1 (murine model) | Cisplatin | Nanogel loaded lidocaine has a synergistic anticancer effect with co-loaded cisplatin both in vitro and in vivo | N/A |
| Lazo 198552 | In vitro | Leukaemia (L1210 murine) | Lidocaine | 0–10 mM | Cisplatin, bleomycin, mitomycin C, etoposide | Lidocaine potentiates bleomycin, cisplatin and etoposide cytotoxicity | N/A |
| Zeng 202143 | In vitro | Gastric (MKN45) | Lidocaine | 10 mM | Cisplatin, 5-FU | Lidocaine enhanced sensitivity of cells to chemotherapeutic agents | Phosphorylation levels of c-Met and c-Src were reduced by lidocaine treatment |
| Zhang 201940 | In vitro | Choriocarcinoma (JEG-3, JAR) | Lidocaine | 10–1000 μM | 5-FU | Lidocaine potentiated 5-FU cytotoxicity | ATP-binding cassette (ABC) transport protein expression—expression of ABCG2, P-glycoprotein, MRP1, MRP2, PI3K/AKT pathway inhibition |
| Wang 201741 | In vitro | Melanoma (SK-MEL-2) | Lidocaine | 10–1000 μM | 5-FU | Lidocaine enhances sensitivity of melanoma cells to 5-FU | Lidocaine induced expression of miR-493 and downregulated expression of SOX4 perhaps by inactivation of PI3K/AKT and TGF-TGF-β pathways |
| Polekova 199258 | In vitro | Leukaemia (L1210, murine) | Lidocaine | 0–2 mM | Vincristine | Lidocaine reversed cancer cell resistance to vincristine | P-glycoprotein and MDR1 (multidrug resistance) gene expression |
| Kim 201929 | In vitro | Oral SCC (KBV20C, MDR cells) | Lidocaine | 5 μM | Vincristine | Lidocaine had no additional effect on cell viability when combined with vincristine | Inhibition of the P-glycoprotein cell efflux protein |
| Wall 201931 | In vivo | Breast (4T1 murine) | Lidocaine | 1.5 mg kg−1 bolus + 2 mg kg−1 h−1 infusion | Bosutinib | Bosutinib reversed the antimetastatic effect of lidocaine, lidocaine reduced MMP-2 expression | Src, MMP-2/9 inhibition |
| Wall 202130 | In vitro | Breast (4T1 murine) | Lidocaine | 5 μM–3 mM | Bosutinib | No effect of combination therapy at therapeutic concentrations | N/A |
| Han 202262 | Both | Breast cancer (MDA-MB231 and 453) | Lidocaine | 0–3 mM | Palbociclib | Palbociclib effects enhanced by local anaesthetic (in vivo/in vitro) | Inhibition of PI3K/AKT/GSK3B and EMT signalling |
| Yang 201855 | Both | Bladder (BIU-87) | Lidocaine | 1.25–5 mg ml−1in vitro, 2.5–5 mg ml−1in vivo per week | Mitomycin C, pirarubicin | In vitro lidocaine enhances cytotoxicity of both chemotherapeutic agents, in vivo lidocaine/MMC prolonged survival and reduced mean bladder wet weight compared with solo therapy | N/A |
| De Moura 202161 | Both | Melanoma (B16–F10 murine, SK-MEL-103) | Lidocaine | 30 μM–10 mM | Docetaxel (DTX) | Addition of lidocaine to NLC-DTX and HGel-NLC-DTX systems increased their cytotoxicity in vitro; addition of lidocaine decreased tumour growth in vivo | Nanostructured lipid carriers (NLC) combined with the antineoplastic docetaxel, formed a hybrid gel (NLC-in-hydrogel) for topical application |
| Zheng 202056 | In vitro | Melanoma (A375, A431) | Lidocaine, ropivacaine, bupivacaine | 250 μM–2 mM | Dacarbazine, vemurafenib | Ropivacaine and lidocaine (but not bupivacaine) enhanced the antimigratory, antiproliferative and pro-apoptotic effects of vemurafenib and dacarbazine | Ropivacaine and lidocaine decreased RhoA, Rac1, and Ras activity; bupivacaine did not affect RhoA, Rac1, and Ras activity |
| Brummelhuis 202159 | In vitro | Ovarian (OVCAR3, OVCAR5, T47D, KURAMOCHI, JHOS4) | Lidocaine, bupivacaine, benzocaine, procaine | Lidocaine (0.2–125 mM), bupivacaine (6 μM–3.75 mM), benzocaine (8 μM–5 mM), procaine (0.02–12.5 mM) | Carboplatin, paclitaxel | Additive effect of local anaesthetics to chemotherapeutic agent effect | Voltage-gated sodium channel (VGSC) inhibition |
| Lirk 201457 | In vitro | Breast (BT-20, MCF-7) | Lidocaine, bupivacaine, ropivacaine | 10–309.2 μM | Decitabine (DAC) | No effect of local anaesthetic/DAC combination on cell viability, lidocaine and ropivacaine cause DNA demethylation—this effect is additive (but not supra-additive) when lidocaine is combined with DAC | DNA demethylation |
| Dorr 199028 | In vitro | Leukaemia (L-1210, RL-1210) | Lidocaine, procaine | 250–350 μM | Mitomycin C | Local anaesthetics did not reverse resistance to mitomycin-C | P-glycoprotein expression |
| Mizuno 198253 | In vitro | Breast (FM3A murine) | Lidocaine, procaine, dibucaine, butacaine, tetracaine | 0.2 mM–12 mM | Bleomycin | All local anaesthetics enhanced bleomycin cytotoxicity | N/A |
| Mizuno 198254 | In vitro | Breast (FM3A, HeLa) | Lidocaine, procaine, dibucaine, butacaine, tetracaine | 0–10 mM | Peplomycin | All local anaesthetics enhanced the cytotoxicity of peplomycin, this was enhanced further by hyperthermia | N/A |
| Chen 202050 | In vitro | Hepatoma (HepG2, BEL-7402) | Lidocaine, ropivacaine, bupivacaine | 0.05, 0.5, 5 mM | Cisplatin | Chemotherapeutic effect enhanced by local anaesthetics | Unregulated RASSF1A expression |
| Zhu 202042 | In vitro | Oesophageal (OE19, SK-GT-4) | Lidocaine, ropivacaine, bupivacaine, mepivacaine | 10–100 μM | 5-FU, paclitaxel | Local anaesthetics augmented the effects of chemotherapeutic agent drugs in inhibiting growth and inducing apoptosis | Mitochondrial dysfunction and oxidative damage (decreased oxygen consumption rate, increased intercellular ROS and 8-OHdG levels), decreased Rac1 activity, no effect on RhoA |
| Meireles 201860 | In vitro | Prostate (PC3) | Lidocaine, ropivacaine, levobupivacaine | Lidocaine (426.7–853.4 nM), ropivacaine (36.4–273.3 nM), levobupivacaine (43.3–173.4 nM) | Docetaxel | Local anaesthetics enhanced chemo-induced inhibition of cell proliferation | N/A |
| Zheng 201866 | In vitro | Leukaemia (CD34, K562, LAMA84) | Ropivacaine | 100–1000 μM | Dasatinib, imatinib | Local anaesthetic/chemotherapeutic agent combination causes greater growth inhibition and apoptosis induction than either agent used alone | PI3K/Akt/mTOR pathway inhibition, increased caspase-3 activation |
| Gong 201865 | In vitro | Breast (MDA-MB-468, SkBr) | Ropivacaine | 0.1–1 mM | 5-FU | Enhanced effects of 5-FU on inhibiting cell growth, survival, and colony formation | Inhibition of mitochondrial respiration (inhibition of phosphorylation of Akt, mTOR, rS6, and EBP1) |
| Dan 201867 | In vitro | Gastric cancer (SNU1, AGS) | Bupivacaine | 10 μM–5 mM | 5-FU | Inhibitory chemotherapeutic effects augmented by bupivacaine | Inhibition of RhoA/ROCK/MLC |