Bashash Davood, Zareii Mohadeseh, Safaroghli-Azar Ava, Omrani Mir Davood, Ghaffari Seyed H
a Department of Hematology and Blood Banking, School of Allied Medical Sciences , Shahid Beheshti University of Medical Sciences , Tehran , Iran.
b Department of Medical Genetics, Faculty of Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran.
Hematology. 2017 Jul;22(6):330-340. doi: 10.1080/10245332.2016.1275426. Epub 2017 Jan 5.
Interest into targeting telomerase in cancer has increased by the recent disclosure that elevated telomerase activity is associated with disease recurrence and poor outcome in cancers. In addition, cellular acquisition of unlimited replicative potential, which is closely related to the maintenance of telomeres mostly via the reactivation of telomerase, has been shown to confer loss of sensitivity to a wide range of anti-neoplastic agents.
To evaluate whether telomerase inhibition using non-nucleosidic inhibitor of telomerase BIBR1532 could enhance cytotoxic effect of doxorubicin in acute lymphoblastic leukemia, Nalm-6 pre-B ALL cells were subjected to combination treatment and subsequent cell viability, growth kinetics, caspase-3 activity, and transcriptional alteration of p73, p21, FOXO3a, c-Myc, hTERT, and other apoptosis-related target genes were investigated.
Combination of BIBR1532 with doxorubicin produced a synergistic anticancer effect probably through induction of p73. Transcription factor p73 not only suppressed the proliferative capacity of the cells through induction of p21-mediated G1 arrest, but also down-regulated the mRNA level of hTERT and c-Myc. Our results also report that BIBR1532 induced a caspase-dependent apoptosis, at least partially, through heightened ROS levels, and noteworthy enhanced the pro-oxidant property of doxorubicin. In harmony, transcriptional repression of survivin could be a probable underlying mechanism for the induction of apoptosis through shifting the ratio of death promoters to death repressors via alteration of Bax and Bcl2 expression.
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.
近期有研究表明，端粒酶活性升高与癌症疾病复发及不良预后相关，这使得针对癌症中端粒酶的研究兴趣日益增加。此外，细胞获得无限增殖潜能与端粒的维持密切相关，而这主要通过端粒酶的重新激活实现，并且已证明这种潜能会导致细胞对多种抗肿瘤药物产生耐药性。
为评估使用端粒酶非核苷抑制剂BIBR1532抑制端粒酶是否能增强阿霉素对急性淋巴细胞白血病的细胞毒性作用，对Nalm-6前B淋巴细胞白血病细胞进行联合治疗，随后研究细胞活力、生长动力学、半胱天冬酶-3活性以及p73、p21、FOXO3a、c-Myc、hTERT和其他凋亡相关靶基因的转录变化。
BIBR1532与阿霉素联合使用可能通过诱导p73产生协同抗癌作用。转录因子p73不仅通过诱导p21介导的G1期阻滞抑制细胞增殖能力，还下调hTERT和c-Myc的mRNA水平。我们的研究结果还表明，BIBR1532至少部分通过提高活性氧水平诱导半胱天冬酶依赖性凋亡，并且显著增强了阿霉素的促氧化特性。同时，通过改变Bax和Bcl2的表达来改变死亡促进因子与死亡抑制因子的比例，可能是survivin转录抑制诱导凋亡的潜在机制。
总体而言，BIBR1532与阿霉素联合使用似乎可能是急性淋巴细胞白血病的一种新型治疗策略，在不久的将来可能应用于临床。
