One of the major controversies of contemporary medicine is created by an increased consumption of nicotine and growing evidence of its connection to cancer, which urges elucidation of the molecular ...mechanisms of oncogenic effects of inhaled nicotine. Current research indicates that nicotinergic regulation of cell survival and death is more complex than originally thought, because it involves signals emanating from both cell membrane (cm)- and mitochondrial (mt)-nicotinic acetylcholine receptors (nAChRs). In this study, we elaborated on the novel concept linking cm-nAChRs to growth promotion of lung cancer cells through cooperation with the growth factor signaling, and mt-nAChRs - to inhibition of intrinsic apoptosis through prevention of opening of mitochondrial permeability transition pore (mPTP).
Experiments were performed with normal human lobar bronchial epithelial cells, the lung squamous cell carcinoma line SW900, and intact and NNK-transformed immortalized human bronchial cell line BEP2D.
We demonstrated that the growth-promoting effect of nicotine mediated by activation of α7 cm-nAChR synergizes mainly with that of epidermal growth factor (EGF), α3 - vascular endothelial growth factor (VEGF), α4 - insulin-like growth factor I (IGF-I) and VEGF, whereas α9 with EGF, IGF-I and VEGF. We also established the ligand-binding abilities of mt-nAChRs and demonstrated that quantity of the mt-nAChRs coupled to inhibition of mPTP opening increases upon malignant transformation.
These results indicated that the biological sum of simultaneous activation of cm- and mt-nAChRs produces a combination of growth-promoting and anti-apoptotic signals that implement the tumor-promoting action of nicotine on lung cells. Therefore, nAChRs may be a promising molecular target to arrest lung cancer progression and re-open mitochondrial apoptotic pathways.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and ...increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.
Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series.
The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio HR, 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis.
The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.
Abstract We present a technology and magneto-mechanical milling chamber for the magneto-mechano-chemical synthesis (MMCS) of magneto-sensitive complex nanoparticles (MNC) comprising nanoparticles Fe3 ...O4 and anticancer drug doxorubicin (DOXO). Magnetic properties of MNC were studied with vibrating magnetometer and electron paramagnetic resonance. Under the influence of mechano-chemical and MMCS, the complex show a hysteresis curve, which is typical for soft ferromagnetic materials. We also demonstrate that Lewis lung carcinoma had a hysteresis loop typical for a weak soft ferromagnet in contrast to surrounding tissues, which were diamagnetic. Combined action of constant magnetic field and radio frequency moderate inductive hyperthermia (RFH) below 40 °C and MNC was found to induce greater antitumor and antimetastatic effects as compared to conventional DOXO. Radiospectroscopy shows minimal activity of FeS-protein electron transport chain of mitochondria, and an increase in the content of non-heme iron complexes with nitric oxide in the tumor tissues under the influence of RFH and MNC. From the Clinical Editor This study reports on the top-down synthesis of magneto-sensitive complex nanoparticles comprised of Fe3 O4 nanoparticles and doxorubicin. Authors also found that Lewis lung carcinoma had a hysteresis loop typical for a weak soft ferromagnet in contrast to surrounding tissues, which were diamagnetic. Combined action of constant magnetic field and radio frequency induced moderate hyperthermia induced both antitumor and antimetastatic effects greater than conventional DOX alone.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although the role of nicotine as a carcinogen is debatable, it is widely accepted that it contributes to cancer by promoting growth and survival of mutated cell clones and protecting them from the ...chemo- and radiotherapy-induced apoptosis. On the cell membrane (cm), the nicotinic acetylcholine (ACh) receptors (nAChRs) implement upregulation of proliferative and survival genes. Nicotine also can permeate cells and activate mitochondrial (mt)-nAChRs coupled to inhibition of the mitochondrial permeability transition pore (mPTP) opening, thus preventing apoptosis. In this study, we sought to pin down principal mechanisms mediating the tumor-promoting activities of nicotine resulting from activation of cm- and mt-nAChRs in oral and lung cancer cells, SCC25 and SW900, respectively. Activated cm-nAChRs were found to form complexes with receptors for EGF and VEGEF via the α7 and β2 nAChR subunits, respectively, whereas activated mt-nAChRs physically associated with the intramitochondrial protein kinases PI3K and Src via the α7 and β4 subunits. This was associated with upregulated expression of cyclin D1/activation of ERK1/2 and inhibition of mPTP opening, respectively, as well as upregulated proliferation and resistance to H2O2-induced apoptosis. The molecular synergy between cm-nAChRs and growth factor receptors helps explain how one biological mediator, such as ACh, can modulate activity of the other, such as a growth factor, and vice versa. Establishment of functional coupling of mt-nAChRs to regulation of mPTP opening provides a novel mechanism of nicotine-dependent protection from cell death. Further elucidation of this novel mechanism of tumor-promoting activities of nicotine should have a strong translational impact, because extraneuronal nAChRs may provide a novel molecular target to prevent, reverse, or retard progression of both nicotine-related and unrelated cancers.
•Nicotine increases number of both oral and lung cancer cells and their resistance to apoptosis.•Activation of cell membrane nicotinic acetylcholine receptors (nAChRs)s results in their association with EGF and VEGEF receptors via α7 and β2 nAChR subunits.•Synergistic signaling through cell membrane nAChRs and growth factor receptors upregulates cyclin D1 and activates ERK1/2.•Activation of mitochondrial nAChRs results in their association with intramitochondrial PI3K and Src via α7 and β4 subunits.•Activation of mitochondrial nAChRs blocks mitochondrial permeability transition pore and prevents cytochrome c release.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Because cholinergic drugs are used in ophthalmology and cholinergic stimulation has been shown to facilitate epithelialization of mucocutaneous wounds, we performed a systematic analysis of ...components of the cholinergic network of human and murine corneal epithelial cells (CECs) and determined the role of autocrine and paracrine acetylcholine (ACh) in regulation of CEC motility.
We investigated the expression of ACh receptors at the mRNA and protein levels in human immortalized CECs, localization of cholinergic molecules in normal and wounded murine cornea, and the effects of cholinergic drugs on CEC directional and random migration in vitro, intercellular adhesion, and expression of integrin αV and E-cadherin.
We demonstrated that corneal epithelium expresses the ACh-synthesizing enzyme choline acetyltransferase, the ACh-degrading enzyme acetylcholinesterase, two muscarinic ACh receptors (mAChRs), M3 and M4, and several nicotinic ACh receptors (nAChRs), including both α7- and α9-made homomeric nAChRs and predominantly the α3β2±α5 subtype of heteromeric nAChRs. Wounding affected the expression patterns of cholinergic molecules in the murine corneal epithelium. Constant stimulation of CECs through both muscarinic and nicotinic signaling pathways was essential for CEC survival and both directional and random migration in vitro. Both α7 and non-α7 nAChRs elicited chemotaxis, with the α7 signaling exhibiting a stronger chemotactic effect. Cholinergic stimulation of CECs upregulated expression of the integrin and cadherin molecules involved in epithelialization. We found synergy between the proepithelialization signals elicited by different ACh receptors expressed in CECs.
Simultaneous stimulation of mAChRs and nAChRs by ACh may be required to synchronize and balance ionic and metabolic events in a single cell. Localization of these cholinergic enzymes and receptors in murine cornea indicated that the concentration of endogenous ACh and the mode of its signaling differ among corneal epithelial layers. Elucidation of the signaling events elicited upon agonist binding to corneal mAChRs and nAChRs will be crucial for understanding the mechanisms of ACh signaling in CECs, which has salient clinical implications.
A search for novel and more efficient therapeutic modalities of inflammatory bowel disease (IBD) is one of the most important tasks of contemporary medicine. The anti-inflammatory action of nicotine ...in IBD might be therapeutic, but its toxicity due to off-target and nonreceptor effects limited its use and prompted a search for nontoxic nicotinergic drugs. We tested the hypothesis that SLURP-1 and -2—the physiological nicotinergic substances produced by the human intestinal epithelial cells (IEC) and immunocytes—can mimic the anti-inflammatory effects of nicotine. We used human CCL-241 enterocytes, CCL-248 colonocytes, CCRF-CEM T-cells, and U937 macrophages. SLURP-1 diminished the TLR9-dependent secretion of IL-8 by CCL-241, and IFNγ-induced upregulation of ICAM-1 in both IEC types. rSLURP-2 inhibited IL-1β-induced secretion of IL-6 and TLR4- and TLR9-dependent induction of CXCL10 and IL-8, respectively, in CCL-241. rSLURP-1 decreased production of TNFα by T-cells, downregulated IL-1β and IL-6 secretion by macrophages, and moderately upregulated IL-10 production by both types of immunocytes. SLURP-2 downregulated TNFα and IFNγR in T-cells and reduced IL-6 production by macrophages. Combining both SLURPs amplified their anti-inflammatory effects. Learning the pharmacology of SLURP-1 and -2 actions on enterocytes, colonocytes, T cells, and macrophages may help develop novel effective treatments of IBD.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Previous studies revealed association of lung cancer risk with single nucleotide polymorphisms (SNPs) in chromosome 15q25 region containing CHRNA5–CHRNA3–CHRNB4 nicotinic acetylcholine receptor ...(nAChR) subunit gene cluster. The genetic variations in other lung nAChRs remained unknown. In this study, we perform case-control analysis of CHRNA9 and CHRNA3 genes using 340 non-small cell lung cancer cases and 435 controls.
All exons, 3′UTR, intron 1 and parts of other introns surrounding exons 2–5 of CHRNA9 gene as well as exons 2, 3 of CHRNA3 gene and parts of surrounding intronic regions were sequenced. The study was controlled for gender, age and ethnicity related differences. Each SNP in analyzed groups was assessed by allele frequency, genotype distribution and haplotype analysis.
The case-control analysis revealed that an increased risk is associated with two SNPs in CHRNA9, rs56159866 and rs6819385, and one in CHRNA3, rs8040868. The risk was reduced for three SNPs in CHRNA9, rs55998310, rs56291234, and newly discovered rs182073550, and also in carriers of the haplotype NP_060051.2 containing ancestral N442 variant of α9.
The nonsynonymous substitutions can produce receptors exhibiting unique ligand-binding and downstream signaling characteristics, synonymous as well all intronic SNPs may affect protein production at the transcriptional and/or translational levels, or just manifest association with cancer by genetic linkage to other alleles. Elucidation of the mechanisms by which individual genetic variations in α9 affect predisposition to lung cancer may lead to development of personalized approaches to cancer prevention and treatment as well as protection against tobacco consumption.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A comparative study of magnetic properties using the method of magnetometry with vibration magnetometer and spectra of electron paramagnetic resonance (EPR) nanocomplexes (NCs) of nanoparticles ...Fe2O3, Fe3O4 and antitumor antibiotic doxorubicin (DOXO) have shown that changes in saturation magnetic moments are similar to changes in integral intensity of EPR spectra. The greatest magnetic moments of saturation and integral intensity of EPR spectra were demonstrated by samples of Fe3O4 in NC with doxorubicin, which had the highest antitumor effect in radiofrequency hyperthermia of Walker-256 carcinosarcoma. The presented research provides the evidence of stronger antitumor effect of Fe3O4 and DOXO NC in comparison to NC from γ-Fe2O3 and DOXO at combined action of constant magnetic field and electromagnetic field. This can be a basis for development of bioengineering technology of magnetic cancer nanotherapy in conditions of moderate hyperthermia (< 39°C).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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