Nicotine increases survival in human colon cancer cells treated with chemotherapeutic drugs

Toxicol In Vitro. 2013 Dec;27(8):2256-63. doi: 10.1016/j.tiv.2013.09.020. Epub 2013 Oct 2.


Cigarette smoking is implicated in the development of colon cancer. Furthermore, nicotine increases cell proliferation and inhibits apoptosis through α7-nicotinic acetylcholine receptor (α7-nAChR) activation in human colon carcinoma cells. An open issue is whether nicotine interfere with colorectal cancer pharmacological treatment, by inhibiting drug-mediated apoptosis. To assess this hypothesis, we evaluated nicotine effect on Caco-2 and HCT-8 colon cancer cells, treated with 5-Fluorouracil (5-FU) and Camptothecin (CPT), chemotherapeutics commonly utilized as adjuvant treatment of colon cancer. Nicotine decreased anti-proliferative and pro-apoptotic effects exerted by chemotherapeutics on both cell lines. These effects partially reverted by exposure to α-bungarotoxin (α-BTX), an inhibitor of α7-nAChR. Nicotine addition to Caco-2 and HCT-8, treated with 5-FU or CPT, decreased the cleavage of substrate of caspase 3 and 7, poly-ADP-ribose polymerase (PARP). Moreover, P-ERK/ERK ratio was modified by nicotine addition to 5-FU and CPT treated cells in an opposite manner. However, when co-administrating PD98059, an ERK phosphorylation inhibitor, an increased apoptosis was observed. In Caco-2 and HCT-8 nicotine reverted 5-FU and CPT apoptotic effects through AKT phosphorylation, as demonstrated by apoptotic increase in presence of LY294002, an AKT phosphorylation inhibitor. Nicotine interfered with colorectal cancer pharmacological treatment in vitro by inhibiting apoptosis induced by chemotherapeutic drugs. Nicotine anti-apoptotic effects were exerted through ERK and AKT pathway activation.

Keywords: 5-Fluorouracil; AKT; Apoptosis; Camptothecin; ERK; Nicotine.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caco-2 Cells
  • Camptothecin / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Colonic Neoplasms
  • Drug Interactions
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluorouracil / pharmacology*
  • Humans
  • Nicotine / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism


  • Antineoplastic Agents
  • alpha7 Nicotinic Acetylcholine Receptor
  • Nicotine
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Fluorouracil
  • Camptothecin