Antidepressants synergize with chemotherapy against cancerstem cells
Antidepressants synergize with chemotherapy against cancerstem cells
In a recent report [1], the antidepressant drug
desmethylclomipramine has shown an interesting
synergistic effect with cisplatin, gemcitabine or
placlitax on lung cancer stem cells. The fact that
antidepressant drugs potentiate chemotherapy in poorly
responding cancer is of major relevance, and opens up
potential innovative therapeutic effects. But what are
the underlying molecular mechanisms for this therapy?
Can this be transferred to other poorly responding
cancers?
We originally identified the HECT containing ITCH as
the ubiquitin E3 ligase responsible for the degradation
of p63 and p73, and, based on that, we performed an
high throughput (HTS) screening using an ELISA-based
HTS with purified recombinant proteins and GST-autoubiquitylation as readout for ITCH activity [2]. The
automated HTS on a 22,000 compound library was
robust, according to an average recorded Z’ of 0.7
(range 0.5-0.7), and resulted in the identification of 46
compounds showing <50% residual activity, 20 of
which were confirmed at single point, and 6 of these
showed a dose-dependent inhibition of ITCH. The most
active validated inhibitors were the antidepressant drugs
clomipramine, norclomipramine and their active
metabolite desmethylclomipramine [2]. Interestingly,
the validation and analysis of the results revealed
clomipramine as a regulator of autophagy [2-3]. This
was an intriguing observation as clomipramine has been
used for over 40 years for the treatment of patients with
psychiatric disorders, with a long-standing record of
tolerance and safety. Antidepressants are known to act
on the serotonin uptake, so the inhibition of an E3 ligase
would suggest that either there is an alternative mode of
action, or that an ITCH-related E3 ligase is involved in
the process, for example as a regulator of the receptor or
of the intracellular recycling pathway. Still, the
regulation of autophagy opens interesting opportunities
for cancer therapy based on the evidence that autophagy
inhibitors potentiate the effect of chemotherapy. Indeed
several clinical trials are under way in phase I-II using
chloroquine to potentiate chemotherapy (e.g.
ClinicalTrials.gov Identifier: NCT01510119,
NCT01480154, NCT01023477, NCT02421575,
NCT01649947). In vitro, clomipramine does potentiate
the effect of chemotherapeutic agents on differen bladder, breast, prostate cancer cell lines [2]. However,
to be more effective, this effect should be tested on
cancer stem cells. And indeed, the work of BongiornoBorbone et al. [1] revealed that clomipramide
compounds have a significant effect on the growth
properties of lung cancer stem cells isolated from nonsmall-cell lung cancers’ surgical specimens.
Desmethylclomipramine, by interfering with the
autophagic flux and blocking the degradation of the
autophagic cargo, decreases the stemness potential of
cancer stem cells and increases the cytotoxic effect of
conventional chemotherapeutic agents on lung cancer
[1]. To check whether this effect is due to a selective
inhibition of ITCH itself and not to another off target
effect, including the inhibition of other HECTcontaining E3 ubiquitin ligases, the authors have
silenced ITCH. The results indicate that the silencing of
ITCH is sufficient to phenocopy the effect of
clomipramide. Moreover, the analysis of the expression
of ITCH in two distinct data sets of lung
adenocarcinoma (GSE31210 and GSE11969)
demonstrates that the expression of ITCH is a
significant negative prognostic marker, affecting long
term Kaplan-Maier survival. https://www.aging-us.com/issue/v7i12
When general population refer to contemporary medicine, precision plays one of the most crucial roles and people’s lives are directly dependent on it. Hence, any researches pertaining to medicine are required to comply with the top standards. The problem today is that any recommendations of researches can be published online and used as a reference without being adequately verified and validated. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this issue and tried to come up with an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been founded back in 2010. The key principle of this journal is based on Altmetric scores that are used as a quality indicator. That helps both readers and authors to verify publications with Altmetric Article Reports that create “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a complete publications list with respective scores higher than 100 as well as reports mentioned previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the necessary assistance to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was released back in 2018 by Oncotarget and completed by several experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The paper has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are aiming to comprehend the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hereby, the paper about melanoma, was used for citations in different news articles 69 times. Besides that, it was quoted in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This research has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get helpful scientific facts. Oncotarget is glad to have the chance to share with online viewers this highly appreciated and top-quality information, that is trustworthy and reliable.
oncotarget removed from pubmed Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
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