Lidocaine exerts anticancer activity in bladder cancer by targeting isoprenylcysteine carboxylmethyltransferase (ICMT)

Teng, Xiao-dan; Yang, Liu; Wang, Liping; Wang, Guonian

doi:10.21037/tau-21-893

Cited by 9 publications

(6 citation statements)

References 23 publications

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“…Lidocaine induced the highest Ca 2+ response among all compounds screened (at their maximum concentrations in aqueous solution), including denatonium benzoate (non-T2R14 agonist whose Ca 2+ response is dependent on T2R4 in these cells [1]), thujone (T2R14 agonist), flufenamic acid (T2R14 agonist), and ATP (purinergic receptor agonist) [57, 60, 61] (Fig 1A-C). Dose dependent Ca 2+ responses were recorded with lidocaine ranging from 100 µM to 10 mM, with 10 mM evoking the highest response [62, 63] (Fig 1D & E; Supplemental Fig 1A-C). At both 5 and 10 mM, lidocaine induced higher Ca 2+ responses than denatonium benzoate (Fig 1D-G).…”

Section: Resultsmentioning

confidence: 99%

Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Through Activation of Bitter Taste Receptor T2R14

Miller

Mueller

Holivert

et al. 2022

Preprint

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Head and Neck Squamous Cell Carcinomas (HNSCCs) have high mortality due to late stage diagnosis, high metastasis rates, and poor treatment options. Current therapies are invasive and aggressive, leading to a severe decline in patient quality of life (QoL). It is vital to create new therapies that are both potent and localized and/or targeted to prolong survival while maintaining QoL. Lidocaine is a local anesthetic used in HNSCC surgery settings. Lidocaine also activates bitter taste (taste family 2) receptor 14 (T2R14). T2Rs are G-protein coupled receptors (GPCRs) that increase intracellular Ca2+ when activated. T2Rs are expressed in mucosal epithelia, including internal regions of the head and neck, and are accessible drug targets. Here, we show that lidocaine increases intracellular Ca2+ and decreases cAMP in several HNSCC cell lines. Ca2+ release from the ER results in Ca2+ uptake into the mitochondria. Ca2+ mobilization is blocked with GPCR inhibitors and T2R14 antagonist, 6-methoxyflavanone. Lidocaine activation of T2R14 depolarizes the mitochondrial membrane, inhibits cell proliferation, and induces apoptosis. Lidocaine activates caspase-3 and -7 cleavage and also increases total caspase protein levels despite no changes in mRNA production. Both total and cleaved caspase products were upregulated even in the presence of cycloheximide, an inhibitor of protein synthesis. This suggests inhibition of the ubiquitin-proteasome system. It is vital to understand Lidocaine-induced apoptosis in HSNCCs to utilize its chemotherapeutic effects as a treatment option. In addition, future studies on T2R14 expression in HNSCC patients could provide insight for implementing lidocaine as a targeted topical therapy.

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Section: Resultsmentioning

confidence: 99%

Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Through Activation of Bitter Taste Receptor T2R14

Miller

Mueller

Holivert

et al. 2022

Preprint

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“…[28][29][30] Furthermore, lidocaine possesses multiple functions, including reducing the release of oxygen free radicals, inhibiting neutrophil adhesion and aggregation, and stabilizing cell membranes, thereby exerting anti-inflammatory effects in various stages of the inflammatory response. 31,32 These findings suggest that lidocaine may exert its beneficial effects by modulating sensory signaling pathways involved in pain perception within the gastrointestinal tract. However, whether lidocaine can protect intestinal barrier in IBS deserves further exploration.…”

Section: Introductionmentioning

confidence: 95%

“…Several studies have demonstrated that intrarectal lidocaine administration effectively reduces abdominal pain and improves visceral hyperalgesia in IBS patients 28–30 . Furthermore, lidocaine possesses multiple functions, including reducing the release of oxygen free radicals, inhibiting neutrophil adhesion and aggregation, and stabilizing cell membranes, thereby exerting anti‐inflammatory effects in various stages of the inflammatory response 31,32 . These findings suggest that lidocaine may exert its beneficial effects by modulating sensory signaling pathways involved in pain perception within the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

Lidocaine ameliorates intestinal barrier dysfunction in irritable bowel syndrome by modulating corticotropin‐releasing hormone receptor 2

Wang,

Qiao,

Yao

et al. 2023

Neurogastroenterology Motil

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BackgroundIntestinal barrier dysfunction is a prevalent pathogenic factor underlying various disorders. Currently there is no effective resolution. Previous studies have reported the potential anti‐inflammatory properties of lidocaine and its ability to alleviate visceral hypersensitivity in individuals with irritable bowel syndrome (IBS). Therefore, our study will further verify the effect of lidocaine on intestinal barrier dysfunction in IBS and investigate the underlying mechanisms.MethodsIn this study, we investigated the role of lidocaine by assessing visceral hypersensitivity, body weight, inflammatory factors, fluorescein isothiocyanate‐dextran 4000 (FD4) flux, tight junctions (TJs) and spleen and thymus index in rats subjected to water avoidance stress (WAS) to mimic intestinal barrier dysfunction in IBS with and without lidocaine. In vitro, we investigated the role of corticotropin‐releasing hormone receptor 2 (CRHR2) in lidocaine‐treated Caco2 cells using small interfering RNA (siRNA) targeting CRHR2.Key ResultsIn WAS rats, lidocaine significantly restored weight loss, damaged TJs, spleen index and thymus index and inhibited abdominal hypersensitivity as well as blood levels of markers indicating intestinal permeability, such as diamine oxidase (DAO), D‐lactic acid (D‐Lac) and lipopolysaccharide (LPS). Consequently, the leakage of FD4 flux from intestine was significantly attenuated in lidocaine group, and levels of intestinal inflammatory factors (IL‐1β, IFN‐γ, TNF‐α) were reduced. Interestingly, lidocaine significantly suppressed corticotropin‐releasing hormone (CRH) levels in lamina propria cells, while the CRH receptor CRHR2 was upregulated in intestinal epithelial cells. In vitro, lidocaine enhanced the expression of CRHR2 on Caco‐2 intestinal epithelial cells and restored disrupted TJs and the epithelial barrier caused by LPS. Conversely, these effects were diminished by a CRHR2 antagonist and siRNA‐CRHR2, suggesting that the protective effect of lidocaine depends on CRHR2.Conclusions and InferencesLidocaine ameliorates intestinal barrier dysfunction in IBS by potentially modulating the expression of CRHR2 on intestinal epithelial cells.

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“…Previous findings suggest that lidocaine affects BC cell proliferation by regulating the cell cycle and the Bax/Bcl-2 ratio. Lidocaine downregulates ICMT and inhibits BC cell proliferation ( 92 , 93 ). In conclusion, postoperative infusion of lidocaine in combination with other chemotherapeutic agents may be more effective than monotherapy in the treatment of BC, and further studies are necessary to explore this possibility.…”

Section: Adjuvant Drugsmentioning

confidence: 99%

Perfusion drugs for non‑muscle invasive bladder cancer (Review)

Qian,

Zhang,

Cao

et al. 2024

Oncol Lett

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The high recurrence rate and poor prognosis of non-muscle invasive bladder cancer (BC) are challenges that need to be urgently addressed. Transurethral cystectomy for bladder tumors is often combined with bladder perfusion therapy, which can effectively reduce the recurrence and progression rates of BC. The present review integrated and analyzed currently available bladder perfusion drugs, mainly including chemotherapeutic agents, immunotherapeutic agents and other adjuvant perfusion drugs. Bacillus Calmette-Guerin (BCG) perfusion was the pioneering immunotherapy for early BC and still ranks high in the selection of perfusion drugs. However, BCG infusion has a high toxicity profile and has been shown to be ineffective in some patients. Due to the limitations of BCG, new bladder perfusion drugs are constantly being developed. Immunotherapeutic agents have opened a whole new chapter in the selection of therapeutic agents for bladder perfusion. The present review explored the mechanism of action, clinical dosage and adverse effects of a variety of bladder perfusion drugs currently in common use, described combined perfusion and compared the effects of certain drugs on BC.

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Lidocaine exerts anticancer activity in bladder cancer by targeting isoprenylcysteine carboxylmethyltransferase (ICMT)

Cited by 9 publications

References 23 publications

Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Through Activation of Bitter Taste Receptor T2R14

Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Through Activation of Bitter Taste Receptor T2R14

Lidocaine ameliorates intestinal barrier dysfunction in irritable bowel syndrome by modulating corticotropin‐releasing hormone receptor 2

Perfusion drugs for non‑muscle invasive bladder cancer (Review)

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