Inhibition of telomerase using BIBR1532 enhances doxorubicin-induced apoptosis in pre-B acute lymphoblastic leukemia cells

Bashash, Davood; Zareii, Mohadeseh; Safaroghli‐Azar, Ava; Omrani, Mir Davood; Ghaffari, Seyed H.

doi:10.1080/10245332.2016.1275426

Cited by 24 publications

(20 citation statements)

References 42 publications

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“…Telomerase is activated in the majority of human malignancies (reviewed in [ 50 ]). Combining telomerase inhibition with apoptosis-inducing drug treatments was shown to increase cell death compared to drug treatment alone ([ 26 , 27 ] and refs. therein).…”

Section: Resultsmentioning

confidence: 99%

“…The prepared inducible HMGB-shRNA constructs were then tested to determine which had the most efficient HMGB silencing. The impact was investigated using at least two different shRNA HMGB constructs for a given HMGB gene along with “scrambled” shRNA controls previously tested in several human cell lines [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The sense and antisense strands containing the shRNA-expressing sequence targeting human HMGB1 , HMGB2 , or both HMGB1 and HMGB2 were annealed and ligated into the BglII/HindIII-linearized pSuperior-puro vector ( ), as detailed in [ 10 ].…”

Section: Methodsmentioning

confidence: 99%

“…Etoposide can induce DNA damage-induced apoptosis in hESCs via the activation of both caspase-3 and transcription-dependent functions of p53 [ 25 ]. The combination of telomerase inhibition with apoptosis-inducing drug treatments was shown to increase cell death compared to drug treatment alone ([ 26 , 27 ] and refs. therein).…”

Section: Introductionmentioning

confidence: 99%

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Nonhistone Proteins HMGB1 and HMGB2 Differentially Modulate the Response of Human Embryonic Stem Cells and the Progenitor Cells to the Anticancer Drug Etoposide

et al. 2020

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HMGB1 and HMGB2 proteins are abundantly expressed in human embryonic stem cells (hESCs) and hESC-derived progenitor cells (neuroectodermal cells, hNECs), though their functional roles in pluripotency and the mechanisms underlying their differentiation in response to the anticancer drug etoposide remain to be elucidated. Here, we show that HMGB1 and/or HMGB2 knockdown (KD) by shRNA in hESCs did not affect the cell stemness/pluripotency regardless of etoposide treatments, while in hESC-derived neuroectodermal cells, treatment resulted in differential effects on cell survival and the generation of rosette structures. The objective of this work was to determine whether HMGB1/2 proteins could modulate the sensitivity of hESCs and hESC-derived progenitor cells (hNECs) to etoposide. We observed that HMGB1 KD knockdown (KD) and, to a lesser extent, HMGB2 KD enhanced the sensitivity of hESCs to etoposide. Enhanced accumulation of 53BP1 on telomeres was detected by confocal microscopy in both untreated and etoposide-treated HMGB1 KD hESCs and hNECs, indicating that the loss of HMGB1 could destabilize telomeres. On the other hand, decreased accumulation of 53BP1 on telomeres in etoposide-treated HMGB2 KD hESCs (but not in HMGB2 KD hNECs) suggested that the loss of HMGB2 promoted the stability of telomeres. Etoposide treatment of hESCs resulted in a significant enhancement of telomerase activity, with the highest increase observed in the HMGB2 KD cells. Interestingly, no changes in telomerase activity were found in etoposide-treated control hNECs, but HMGB2 KD (unlike HMGB1 KD) markedly decreased telomerase activity in these cells. Changes in telomerase activity in the etoposide-treated HMGB2 KD hESCs or hNECs coincided with the appearance of DNA damage markers and could already be observed before the onset of apoptosis. Collectively, we have demonstrated that HMGB1 or HMGB2 differentially modulate the impact of etoposide treatment on human embryonic stem cells and their progenitor cells, suggesting possible strategies for the enhancement of the efficacy of this anticancer drug.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Nonhistone Proteins HMGB1 and HMGB2 Differentially Modulate the Response of Human Embryonic Stem Cells and the Progenitor Cells to the Anticancer Drug Etoposide

et al. 2020

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“…A large number of small molecules including those screened from chemical library of reverse transcriptase show direct interaction with hTERT. Along this line, a compound (BIBR1532) binds directly to the hTERT and inhibits the catalytic function of telomerase [141,146], promote shortening of telomere and senescence in human cancer cells [142]. However, further studies show that BIBR1532 could be promising when given in combination with traditional chemotherapeutic agents [144,145].…”

Section: Telomerasementioning

confidence: 99%

Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations

Amir

Khan

Queen

et al. 2020

Cells

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Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are replicated by conventional DNA replication, and only the last bit of the lagging strand is synthesized by telomerase (a reverse transcriptase). In addition to replication, telomere maintenance is principally carried out by two key complexes known as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, and TPP1) and CST (CDC13/CTC1, STN1, and TEN1). Shelterin protects the telomere from DNA damage response (DDR) and regulates telomere length by telomerase; while, CST govern the extension of telomere by telomerase and C strand fill-in synthesis. We have investigated both structural and biochemical features of shelterin and CST complexes to get a clear understanding of their importance in the telomere maintenance. Further, we have analyzed ~115 clinically important mutations in both of the complexes. Association of such mutations with specific cellular fault unveils the importance of shelterin and CST complexes in the maintenance of genome stability. A possibility of targeting shelterin and CST by small molecule inhibitors is further investigated towards the therapeutic management of associated diseases. Overall, this review provides a possible direction to understand the mechanisms of telomere borne diseases, and their therapeutic intervention.

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“…Kanser hücreleri üzerinde gösterdiği etki yakın geçmişte çok sayıda preklinik araştırma ile değerlendirilmiştir ve bu inhibitörün birçok kanser türünde tümör hücre büyümesini baskılayabilme özelliğinin çok güçlü olduğu gösterilmiştir Plot (Fl1-A/Fl2-a (18)(19)(20). Ayrıca, BIBR1532'nin kanser kemoterapisinde yardımcı bir ilaç olarak potansiyel bir uygulama bulabileceğini gösteren kanıtlar da bulunmaktadır (21). Çalışmamızda telomeraz inhibitörü BIBR1532 uygulanan CCRF-CEM hücrelerinde hTERT geninin ekspresyon seviyesi kontrole göre 3.1 kat azalmıştır.…”

Section: Tartişma Ve Sonuçunclassified

Telomerase Inhibitor BIBR1532 Increases the Expression of CDH13, DAPK1, NR4A3 Genes in Acute Lymphoblastic Leukemia Cells and Induced Apoptosis

Özateş¹,

Goker²,

Doğan³

et al. 2017

LLM Dergi

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Akut lenfoblastik lösemi (ALL), kemik iliği veya diğer lenfoid dokulardaki lenfoid progenitör hücrelerin farklılaşma ve çoğalma anomalilerinden kaynaklanan hematolojik malignitedir. Telomeraz inhibitörleri çoğalmayı ve büyümeyi önleyen bir diğer önemli antikanser ajanlardır. BIBR1532, keşfedildiği günden beri, oldukça etkili bir hTERT inhibitörü olarak kullanılmaktadır. Bu çalışmada, BIBR1532'nin yetişkin akut lenfoblastik lösemi hücre hattı olan CCRF-CEM üzerindeki sitotoksik etkisinin kontrol grubuyla kıyaslanarak belirlenmesi amaçlanmıştır. Hastalar ve Yöntem: BIBR1532'nin CCRF-CEM hücre hattı üzerindeki etkisi WST-1 analizi ile belirlenmiştir. Apoptozun belirlenmesinde Annexin V yöntemi kullanılmıştır. Gen ekspresyon değişiklikleri gerçek zamanlı polimeraz zincir reaksiyonu (PCR) ile belirlenmiştir. Bulgular: BIBR1532'nin CCRF-CEM hücre hattı üzerindeki IC 50 dozu 48 saat sonunda 89 μM olarak belirlenmiştir. Aynı zamanda apoptozu kontrole göre %7 artırdığı ve CDH13, DAPK1 ve NR4A3 genlerinin ekspresyon seviyelerinde belirgin bir artışa sebep olduğu belirlenmiştir. Sonuç: Sonuç olarak elde ettiğimiz bulgulara göre ALL tedavisinde telomeraz inhibitörü BIBR1532 kullanımı, telomeraz aktivitesini düşürebileceği gibi apoptotik hücre ölümünü de uyarabilir. Ayrıca bu yolakta görevli genlerin anlamlı ekspresyon değişikliğinin olması hastalığın moleküler patolojisinin aydınlatılmasına ve alternatif tedavi hedefi olabilecek genlerin belirlenmesine katkı sağlayabilir.

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Inhibition of telomerase using BIBR1532 enhances doxorubicin-induced apoptosis in pre-B acute lymphoblastic leukemia cells

Abstract: Overall, it seems that combination of BIBR1532 and doxorubicin could be a novel therapeutic strategy for acute lymphoblastic leukemia that may be clinically accessible in the near future.

Cited by 24 publications

References 42 publications

Nonhistone Proteins HMGB1 and HMGB2 Differentially Modulate the Response of Human Embryonic Stem Cells and the Progenitor Cells to the Anticancer Drug Etoposide

Nonhistone Proteins HMGB1 and HMGB2 Differentially Modulate the Response of Human Embryonic Stem Cells and the Progenitor Cells to the Anticancer Drug Etoposide

Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations

Telomerase Inhibitor BIBR1532 Increases the Expression of CDH13, DAPK1, NR4A3 Genes in Acute Lymphoblastic Leukemia Cells and Induced Apoptosis

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