•Nicotine increases proliferation and inhibits apoptosis in human colon carcinoma cells treated with 5-FU and CPT.•Nicotine effects are mediated through the interaction with the α7-nAChR.•Nicotine ...addition to chemotherapeutic agents inhibits apoptosis through ERK and AKT pathways.
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.
Abstract
Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for ...apoptosis/growth inhibition. Over‐expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by
MDM
2.
MDM
2 also acts as E3 ubiquitin ligase, promoting the proteasome‐dependent p53 degradation.
MDM
2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering
MDM
2 in the cytosol, whereas the
PI
3K‐AkT‐dependent
MDM
2 phosphorylation is mandatory for
MDM
2 translocation across the nuclear membrane. In addition,
MDM
2‐dependent targeting of p53 is regulated in a nonlinear fashion by
MDM
2/
MDMX
interplay. Melatonin induces both cell growth inhibition and apoptosis in
MCF
7 breast cancer cells. We previously reported that this effect is associated with reduced
MDM
2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down‐regulates
MDM
2 gene expression and inhibits
MDM
2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt‐
PI
3K‐dependent
MDM
2 phosphorylation. Melatonin induces a 3‐fold increase in both
MDMX
and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin‐treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15‐fold increase in p21 levels was observed in melatonin‐treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the
MDM
2/
MDMX
/p300 pathway, disclosing new insights for understanding its anticancer effect.
Currently, there is no evidence whether ganciclovir, or its oral prodrug valganciclovir, penetrates into the cerebrospinal fluid of human infants treated for congenital cytomegalovirus infection. ...Here, we report a case study providing evidence that ganciclovir, administered as valganciclovir, reaches the infant's cerebrospinal fluid when used at the currently recommended dose for congenital cytomegalovirus infection.
Early onset sepsis (EOS) is a severe problem affecting very low birth weight (VLBW) infants and is associated with a threefold increased risk of mortality. Although advances in perinatal care have ...led to improved survival of VLBW infants over recent decades, survival without major neonatal morbidity has not increased. The authors reviewed the current literature on EOS, focusing on the peculiarities concerning risk factors, etiology, diagnosis, treatment and outcome in very low birth weight infants, and on the recent advances in the management of this condition.
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