Total Pageviews

Sunday, March 3, 2013

Proteasome inhibition as a novel mechanism of the proapoptotic activity of γ-secretase inhibitor I in cutaneous T-cell lymphoma.


Proteasome inhibition as a novel mechanism of the proapoptotic activity of γ-secretase inhibitor I in cutaneous T-cell lymphoma.


2013 Mar 

Source

Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, Copenhagen-2400, Denmark.

Abstract

Background  
We have previously discovered that Notch1 is expressed on malignant T cells in cutaneous T-cell lymphoma(CTCL), and is required for survival of CTCL cell lines. Notch can be inhibited by γ-secretase inhibitors (GSIs), which differ widely in their ability to induce apoptosis in CTCL. Objectives  To investigate whether GSI-I, in addition to inhibiting Notch, induces apoptosis in CTCL by proteasome inhibition, as GSI-I is very potent and has structural similarity to the proteasome inhibitor MG-132. Methods  Cell lines derived from CTCL (MyLa, SeAx, JK, Mac1 and Mac2a) were treated with GSI-I and two other proteasome inhibitors (MG-132 and bortezomib). The effects on cell viability, apoptosis and proteasome activity were measured, as was the impact on the prosurvival, nuclear factor κB (NF-κB) pathway. Results  In CTCL, GSI-I had proteasome-blocking activity with a potency comparable to the proteasome inhibitors MG-132 and bortezomib. 
Proteasome inhibition was the main mechanism responsible for GSI-I-induced cell death, as tiron, a compound known to reverse the effect of MG-132, restored proteasome activity and largely abrogated the cytotoxic effect of GSI-I. Although inactivation of NF-κB is an important mechanism of action for proteasome inhibitors, we demonstrated an apparent activation of NF-κB. Furthermore, we showed that while the tumour suppressor protein p53 was induced during proteasome inhibition, it was dispensable for CTCL apoptosis, as both SeAx cells, which harbour p53 mutations that attenuate the apoptotic capacity, and HuT-78 cells, which have a deleted p53 gene, demonstrated potent apoptotic response. Conclusions  GSI-I represents an interesting drug with a dual mechanism of action comprising inhibition of both Notch and the proteasome.

3 comments:

Unknown said...

Hi there Pat, I was actually just reading a few of your posts and had a quick question about your blog. I was hoping you could email me back when you get the chance, thanks : )

Emmy

AIB FUNDING. said...

HOW I GOT CURED OF HERPES VIRUS.

Hello everyone out there, i am here to give my testimony about a herbalist called Dr Imoloa. i was infected with herpes simplex virus 2 in  2013, i went to many hospitals for cure but there was no solution, so i was thinking on how  i can get a solution out so that my body can be okay. one day i was in the pool side browsing and thinking of where i can get a solution. i go through many website were i saw so many testimonies about dr imoloa on how he cured them. i did not believe but i decided to give him a try, i contacted him and he prepared the herpes for me which i received through DHL courier service. i took it for two weeks after then he instructed me to go for check up, after the test i was confirmed herpes negative. am so free and happy. so, if you have problem or you are infected with any disease kindly contact him on email                      drimolaherbalmademedicine@gmail.com. or  / whatssapp --+2347081986098.
This testimony serve as an expression of my gratitude. he also have
 herbal cure for, FEVER, BODY PAIN, DIARRHOEA, MOUTH ULCER, MOUTH CANCER FATIGUE, MUSCLE ACHES, LUPUS, SKIN CANCER, PENILE CANCER,  BREAST CANCER, PANCREATIC CANCER, CHRONIC KIDNEY DISEASE, VAGINAL CANCER, CERVICAL CANCER, DISEASE, JOINT PAIN, POLIO DISEASE,  PARKINSON'S DISEASE, ALZHEIMER'S DISEASE, BULIMIA DISEASE,   INFLAMMATORY JOINT DISEASE CYSTIC FIBROSIS,  SCHIZOPHRENIA, CORNEAL ULCER, EPILEPSY, FETAL ALCOHOL  SPECTRUM, LICHEN PLANUS, COLD SORE, SHINGLES, CANCER, HEPATITIS A, B.  DIABETES 1/2, HIV/AIDS, CHRONIC RESPIRATORY DISEASE,  CARDIOVASCULAR DISEASE,  NEOPLASMS, MENTAL AND BEHAVIOURAL DISORDER, CHLAMYDIA, ZIKA VIRUS, EMPHYSEMA, TUBERCULOSIS LOW SPERM COUNT, ENZYMA, DRY COUGH, ARTHRITIS, LEUKAEMIA, LYME DISEASE, ASTHMA, IMPOTENCE, BARENESS/INFERTILITY, WEAK ERECTION, PENIS ENLARGEMENT. AND SO ON.

Florence said...


I started on COPD Herbal treatment from Ultimate Life Clinic, the treatment worked incredibly for my lungs condition. I used the herbal treatment for almost 4 months, it reversed my COPD. My severe shortness of breath, dry cough, chest tightness gradually disappeared. Reach Ultimate Life Clinic via their website www.ultimatelifeclinic.com . I can breath much better and It feels comfortable!