Antiproliferative Effects of Celecoxib in Hep-2 Cells through Telomerase Inhibition and Induction of Apoptosis

Zhao, Yongqiang; Feng, Hui; Jia, Tan; Zhang, Hui; Xu, Anting; Zhang, Hailing; Fan, Xiaoxuan

doi:10.7314/apjcp.2014.15.12.4919

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…However, numerous drugs with various other targets have been identified with additional off-target effects on telomerase activity. These include substances which act via downregulation of hTERT gene transcription: the tyrosine kinase inhibitors dasatinib, imatinib, gefitinib, and nilotinib [ 191 , 192 , 193 ]; the ubiquitin/proteasome pathway inhibitor bortezomib; the cytotoxic drugs 5-azacytidine [ 194 ], arsenic trioxide [ 195 ] and temozolomide [ 196 ]; the chemosensitizer suramin [ 197 ]; the non-steroidal anti-inflammatory drugs aspirin [ 198 ], indomethacin [ 198 ], and celecoxib [ 199 ]; the peroxisome proliferator-activated receptor (PPAR) activator troglitazone [ 200 ]; the histone deacetylase inhibitors romidepsin [ 201 ] and vorinostat [ 202 ]; and the mTOR pathway inhibitor rapamycin [ 203 ]. The DNA topoisomerase I inhibitor beta-lapachone [ 204 ] and the DNA crosslinker cisplatin [ 205 ] act via downregulation of hTR gene transcription.…”

Section: Telomerase As a Target For Cancer Treatmentmentioning

confidence: 99%

Therapeutic Targeting of Telomerase

Jäger

Walter

2016

Genes

119

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Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches. Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a ‘mild’ integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

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Section: Telomerase As a Target For Cancer Treatmentmentioning

confidence: 99%

Therapeutic Targeting of Telomerase

Jäger

Walter

2016

Genes

119

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“… 10 COX-2 inhibitors, such as celecoxib, act through the prostaglandin E2–cyclic adenosine monophosphate–protein kinase C–nuclear factor kappa B (NF-κB) pathway regulating the expression of multidrug resistance-associated protein-1 and other cellular proteins abolishing drug resistance. 11 , 12 …”

Section: Discussionmentioning

confidence: 99%

Lenalidomide, celecoxib, and azacitidine therapy for blastic plasmocytoid dendritic cell neoplasm: a case report

García‐Recio¹,

Martínez-Serra²,

Bento³

et al. 2016

OTT

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Blastic plasmocytoid dendritic cell neoplasm is characterized by aggressive behavior with a tendency for systemic dissemination and a predilection for skin, lymph nodes, soft tissues, peripheral blood, or bone marrow. It usually occurs in elderly patients with a mean age between 60 and 70 years. Despite initial response to chemotherapy, the disease regularly relapses with a short median overall survival. Better outcomes have been reported with high-dose acute leukemia-like induction chemotherapy followed by consolidation with allogeneic hematopoietic stem cell transplantation. However, elderly patients are not candidates for intensive therapy or allogeneic stem cell transplantation. So, new active and tolerable drugs are needed. Our case illustrates that one cycle of lenalidomide and celecoxib provides at least a partial cutaneous and hematologic response, but this regimen was discontinued due to toxicity and followed by a consolidation/maintenance phase with azacitidine, thus achieving a final complete response with a much higher than expected progression-free and overall survival in an elderly patient with comorbidities. This information may be useful in the design of treatment approaches for elderly patients with blastic plasmocytoid dendritic cell neoplasm. However, it should be confirmed in clinical trials as well as by optimizing the induction and extending the consolidation/maintenance period to avoid early relapses after discontinuation and improve progression-free survival.

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“…Podczas badań przeprowadzonych w warunkach in vitro i in vivo zaobserwowano regresję nowotworu po podaniu szczepionki. Fragmenty [22][23][24][25][26][27][28] peptydów powstałe po degradacji telomerazy mogą być prezentowane na powierzchni komórek nowotworowych cytotoksycznym limfocytom T CD8+ przez główny kompleks zgodności tkankowej klasy I (ang. major histocompatibility complex, MHC I), co prowadzi do stymulacji układu immunologicznego i atakowania komórek wykazujących ekspresję telomerazy.…”

Section: Telomeraza Jako Cel Terapii Nowotworów Głowy I Szyiunclassified

“…Istnieje wiele różnych strategii terapii wykorzystującej inhibicję telomerazy, od terapii genowej do wykorzystania przeciwutleniaczy i szczepionek. Najważniejszym celem obecnie prowadzonych badań jest opracowanie [22][23][24][25][26][27][28] skutecznych metod wprowadzenia tych molekuł przy jednoczesnym zachowaniu bezpieczeństwa, specyficzności i skuteczności terapeutycznej oraz ograniczeniu efektów ubocznych. Wyżej przedstawione przykłady przeprowadzonych doświadczeń potwierdzają hipotezę o możliwości zahamowania rozrostu tkanki nowotworowej i spadku masy guza poprzez inaktywację telomerazy.…”

Section: Wnioskiunclassified

Telomeraza jako potencjalny cel terapii nowotworów głowy i szyi

Dylawerska

Barczak

Suchorska

2017

LOS

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StreszczenieTelomeraza to duży, złożony kompleks enzymatyczny, który odpowiada za proces syntezy telomerów budujących zakończenia eukariotycznych chromosomów. Podwyższona ekspresja genu kodującego katalityczną podjednostkę tego enzymu -hTERT -jest obserwowana w około 88% przypadków nowotworów rejonu głowy i szyi. Komórki rakowe zyskują wówczas wysoki potencjał replikacyjny, a także zdolność do unikania apoptozy. Zahamowanie aktywności telomerazy w terapii przeciwnowotworowej stało się priorytetem badań naukowych już kilkanaście lat temu. Istnieją różne metody wykorzystujące obniżenie ekspresji telomerazy, od terapii genowej do wykorzystania przeciwutleniaczy. Pomimo wielu danych zebranych w ostatnich latach pojawia się coraz więcej pytań w odniesieniu do roli telomerazy w powstawaniu raka. Należy przeprowadzić więcej szczegółowych badań w celu zrozumienia udziału tego enzymu w procesie rozwoju nowotworu w obrębie narządów głowy i szyi. Celem niniejszego artykułu jest zebranie dotychczasowej wiedzy na temat zastosowania telomerazy w terapii onkologicznej. AbstractTelomerase is an enzymatic complex catalyzing the synthesis of a telomeric DNA, building the ends of an eukaryotic chromosomes. Increased expression of the gene encoding the catalytic subunit of the enzyme -hTERT is observed in approximately 88% of head and neck cancer cases. It leads to the high replication potential and inability to respond to the signals causing apoptosis within the cancer tissues. The use of telomerase in cancer therapy become a priority research over a decade ago. There are many different strategies involving the telomerase inhibitors, gene therapy and antioxidants. Despite the large amount of data collected in recent years, there are more and more questions regarding the role of telomerase in cancerogenesis. More detailed studies must be performed in order to understand the involvement of this enzyme in the process of cancer development within the region of the head and neck.Adres do korespondencji

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Antiproliferative Effects of Celecoxib in Hep-2 Cells through Telomerase Inhibition and Induction of Apoptosis

Cited by 9 publications

References 25 publications

Therapeutic Targeting of Telomerase

Therapeutic Targeting of Telomerase

Lenalidomide, celecoxib, and azacitidine therapy for blastic plasmocytoid dendritic cell neoplasm: a case report

Telomeraza jako potencjalny cel terapii nowotworów głowy i szyi

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