Drug and Alcohol Rehabilitation: Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types.
Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(11): e47519
Sermeus A, Genin M, Maincent A, Fransolet M, Notte A, Leclere L, Riquier H, Arnould T, Michiels C
Hypoxia plays an important role in the resistance of tumour cells to chemotherapy. However, the exact mechanisms underlying this process are not well understood. Moreover, according to the cell lines, hypoxia differently influences cell death. The study of the effects of hypoxia on the apoptosis induced by 5 chemotherapeutic drugs in 7 cancer cell types showed that hypoxia generally inhibited the drug-induced apoptosis. In most cases, the effect of hypoxia was the same for all the drugs in one cell type. The expression profile of 93 genes involved in apoptosis as well as the protein level of BCL-2 family proteins were then investigated. In HepG2 cells that are strongly protected against cell death by hypoxia, hypoxia decreased the abundance of nearly all the pro-apoptotic BCL-2 family proteins while none of them are decreased in A549 cells that are not protected against cell death by hypoxia. In HepG2 cells, hypoxia decreased NOXA and BAD abundance and modified the electrophoretic mobility of BIM(EL). BIM and NOXA are important mediators of etoposide-induced cell death in HepG2 cells and the hypoxia-induced modification of these proteins abundance or post-translational modifications partly account for chemoresistance. Finally, the modulation of the abundance and/or of the post-translational modifications of most proteins of the BCL-2 family by hypoxia involves p53-dependent and -independent pathways and is cell type-dependent. A better understanding of these cell-to-cell variations is crucial in order to overcome hypoxia-induced resistance and to ameliorate cancer therapy.
HubMed – drug
Plasmonic nanobubbles rapidly detect and destroy drug-resistant tumors.
Filed under: Drug and Alcohol Rehabilitation
Theranostics. 2012; 2(10): 976-87
Lukianova-Hleb EY, Ren X, Townley D, Wu X, Kupferman ME, Lapotko DO
The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients’ survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment.
HubMed – drug
Changes in intracellular redox status influence multidrug resistance in gastric adenocarcinoma cells.
Filed under: Drug and Alcohol Rehabilitation
Exp Ther Med. 2012 Aug; 4(2): 291-296
Tai DJ, Jin WS, Wu CS, Si HW, Cao XD, Guo AJ, Chang JC
Multidrug resistance (MDR) to chemotherapeutic agents is a major obstacle for the treatment of various types of cancers. The exact mechanism of MDR has not yet been fully clarified, although it has been frequently associated with the variation of intracellular redox status. The levels of intracellular glutathione (GSH) are considered to play a vital role in the regulation of the intracellular redox status. In our study, we investigated the effects of buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis, and NAC, a cysteine source for GSH synthesis, on sensitive gastric adenocarcinoma cells (SGC7901) and cisplatin-resistant SGC7901/DDP cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The two cell lines were pretreated with various non-toxic concentrations of BSO for 24 h and combined with fluorouracil (5-FU) or mitomycin (MMC) in the presence or absence of NAC before culturing further. After various treatments, the IC(50) values of MMC and 5-FU were calculated and intracellular GSH levels were measured using the glutathione reductase/5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) recycling assay without anticancer drug stimulation under the same microenvironments. The study demonstrated that BSO increased the sensitivity of the cells to chemotherapeutics while NAC exhibited the reverse effect, particularly in drug-resistant cells. It is, therefore, possible that changes in intracellular GSH levels affect the chemosensitivity of the resistant cells to a greater extent than that of their parent cells. This study indicates that variation in the intracellular redox status may be closely correlated with MDR and may provide a valuable basic strategy for anticancer therapy.
HubMed – drug
K(ATP) channels mediate the antihypertrophic effects afforded by ?-opioid receptor stimulation in neonatal rat ventricular myocytes.
Filed under: Drug and Alcohol Rehabilitation
Exp Ther Med. 2012 Aug; 4(2): 261-266
Zhang L, Wang H, Lu M, Wu G, Yang Y, Liu C, Maslov LN
Recent evidence suggests that ?-opioid receptor (OR) agonists and K(ATP) channel activation exert antihypertrophic effects on cardiac myocytes. We studied the role of K(ATP) channels in the antihypertrophic effects of ORs in primary cultures of neonatal rat ventricular myocytes exposed for 48 h to the ?(1) adrenoceptor agonist phenylephrine and the relative contributions of mitochondrial K(ATP) (mitoK(ATP)) and sarcolemmal K(ATP) (sarcK(ATP)). Furthermore, we elucidated the pathway between ORs and K(ATP) channels and their impact on intracellular Ca(2+) ([Ca(2+)](i)) transients. Hypertrophy of cardiomyocytes was characterized by increases in i) total protein content; ii) cell size and iii) [(3)H]leucine incorporation. Phenylephrine (10 ?M) increased the three parameters. Trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid methanesulfonate salt (U50,488H), a selective ?-opioid receptor agonist, prevented phenylephrine-induced hypertrophy and [Ca(2+)](i) transients. The effect of U50,488H was abolished by nor-binaltorphimine, a selective ?-OR antagonist, indicating that the effect was ?-OR-mediated. The protein kinase C inhibitor chelerythrine and the K(ATP) channel inhibitors glibenclamide (50 ?M), a nonselective K(ATP) antagonist, and 5-hydroxydecanoic acid (100 ?M), a mitochondrial selective K(ATP) antagonist, reversed the antihypertrophic effect of U50,488H, and there was no significant difference between the two K(ATP) channel blockers. Moreover, we also determined the expression of the Kir6.2 subunits of the K(ATP) channel, which increased in response to U50,488H in the presence of phenylephrine, but was suppressed by chelerythrine, glibenclamide and 5-hydroxydecanoic acid. U50,488H also attenuated the elevation of [Ca(2+)](i). This study suggests that K(ATP), and particularly the mitochondrial K(ATP,) mediates the antihypertrophic effects of ?-opioid receptor stimulation via the PKC signaling pathway.
HubMed – drug
Olanzapine as a cause of urinary incontinence: a case report.
Filed under: Drug and Alcohol Rehabilitation
Iran J Psychiatry. 2012; 7(3): 146-8
Dada MU, Oluwole LO, Adegun PT, Tareo PO
Olanzapine, an atypical antipsychotic, is one of the most commonly used antipsychotics. Though olanzapine is commonly associated with endocrine side effects, it is generally well tolerated by most patients and is rarely associated with urinary incontinence. This report highlights the case of a 23 -year old male patient with schizophrenia who developed severe urinary incontinence following the use of olanzapine. No medications were given to relieve the incontinence contrary to some other studies where ephedrine was used. Olanzapine was changed to trifluoperazine, and the patient’s condition improved within two days. Urinary incontinence, though uncommon, is an embarrassing side effect of olanzapine which could negatively affect drug compliance. As such, clinicians should enquire about it in order to improve the patient’s health.
HubMed – drug
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