Mitotic Cell Death by Chromosome Fragmentation

Stevens, Joshua B.; Guo, Lei; Bremer, Steven W.; Ye, Karen J.; Xu, Wenxin; Xu, Jing; Sun, Yi; Wu, Gen Sheng; Savaşan, Süreyya; Krawetz, Stephen A.; Ye, Christine J.; Heng, Henry H.Q.

doi:10.1158/0008-5472.can-07-0472

Cited by 90 publications

(94 citation statements)

References 40 publications

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“…Its main mechanism of action occurs through its intercalation between the DNA base pairs, a binding event that takes place during G 2 phase of the cell cycle (Stevens et al, 2007). Such intercalation activity provokes apoptosis through the inhibition of important enzymes involved in cell division, as topoisomerase II (Bodley et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

et al. 2014

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SUMMARYDoxorubicin, an anticancer drug, is widely included in chemotherapy protocols to combat childhood cancer. Carnitine, an important quaternary amine, is present in testis and epididymis and is involved in sperm maturation; it has been used in infertility treatment. In a previous study, our group observed that L-carnitine given before etoposide, another chemotherapeutic drug, reduces the spermatogenic damage and protects germ cells against apoptosis. This study aimed to evaluate the antiapoptotic and cytoprotective actions of L-carnitine in long-and mid-term basis, on the seminiferous epithelium of doxorubicin-treated pre-pubertal rats. Fortyeight 30-day-old male Wistar rats were distributed into four groups: sham-control; doxorubicin; carnitine; carnitine/doxorubicin (L-carnitine injected 1 h before doxorubicin). The rats were submitted to euthanasia at 64 and 100 days of age and their testes were collected for biometric, morphometric, and histopathological analyses. The numerical density of apoptotic germ cells was obtained (TUNEL method). In adult phase (100 days), the following spermatic parameters were analyzed: mature spermatid (19 step) count and sperm daily production per testis; sperm number and transit time through the epididymal caput/corpus and cauda; frequency of morphologically abnormal spermatozoa (from epididymal fluid), as well as sperm DNA integrity (Comet assay). The testicular and spermatic parameters at both ages were improved in rats treated with carnitine before doxorubicin. At 64 days, the TUNEL-positive germ cell frequency was lower in the carnitine/doxorubicin-treated rats comparatively to the doxorubicin-treated rats. At 100 days of age, the sperm DNA fragmentation was also lower in the previously carnitine-treated rats, as evidenced by the analysis of three parameters. Carnitine reduced the late testicular and spermatic damages caused by doxorubicin, probably providing a partial cytoprotection against the deleterious action of doxorubicin administration to pre-pubertal rats. However, further studies shall be undertaken to investigate the protective mechanisms involved in such germ cell preservation.

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Section: Introductionmentioning

confidence: 99%

Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

et al. 2014

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“…Culture conditions for in vitro fertilization represent such an example. Our group recently characterized chromosome fragmentation (C-frag), a form of mitotic cell death distinct from apoptosis, mitotic catastrophe, and premature chromosome condensation (PCC) [Stevens et al 2007;Stevens et al 2010;Stevens et al 2011]. This type of cell death occurs during metaphase where condensed chromosomes are progressively degraded.…”

Section: Various Methods Are Needed To Monitor Genome Integrity Durinmentioning

confidence: 99%

Genome constraint through sexual reproduction: application of 4D-Genomics in reproductive biology

Horne¹,

Abdallah²,

Stevens³

et al. 2013

Systems Biology in Reproductive Medicine

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“…The genome serves as the selective entity and platform for gene interaction, which is much more powerful than individual gene mutations. One way cells can acquire such massive genome alterations, is through a phenomenon termed genome chaos, 25,26,49,50 also referred to as chromoplexy and chromothripsis. 37,38 This process, driven by both internal and external stressors, occurs within the punctuated phase and contributes to the diversity necessary for Current cytogenetics defines a clonal chromosome aberration (CCA) as a given chromosome aberration which can be detected at least twice within 20 to 40 mitotic figures, while a non-clonal chromosome aberration (NCCA) is observed at a frequency less than 4% (less than 2 in 50 mitotic cells examined).…”

Section: Genome Theory Of Cancer Evolution Offers a Genome System Appmentioning

confidence: 99%

Evolutionary mechanism unifies the hallmarks of cancer

Horne

Pollick

Heng

2014

Intl Journal of Cancer

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The basis for the gene mutation theory of cancer that dominates current molecular cancer research consists of: the belief that gene‐level aberrations such as mutations are the main cause of cancers, the concept that stepwise gene mutation accumulation drives cancer progression, and the hallmarks of cancer. The research community swiftly embraced the hallmarks of cancer, as such synthesis has supported the notions that common cancer genes are responsible for the majority of cancers and the complexity of cancer can be dissected into simplified molecular principles. The gene/pathway classification based on individual hallmarks provides explanation for the large number of diverse gene mutations, which is in contrast to the original estimation that only a handful of gene mutations would be discovered. Further, these hallmarks have been highly influential as they also provide the rationale and research direction for continued gene‐based cancer research. While the molecular knowledge of these hallmarks is drastically increasing, the clinical implication remains limited, as cancer dynamics cannot be summarized by a few isolated/fixed molecular principles. Furthermore, the highly heterogeneous genetic signature of cancers, including massive stochastic genome alterations, challenges the utility of continuously studying each individual gene mutation under the framework of these hallmarks. It is therefore necessary to re‐evaluate the concept of cancer hallmarks through the lens of cancer evolution. In this analysis, the evolutionary basis for the hallmarks of cancer will be discussed and the evolutionary mechanism of cancer suggested by the genome theory will be employed to unify the diverse molecular mechanisms of cancer.

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Mitotic Cell Death by Chromosome Fragmentation

Abstract: Cell death plays a key role for both cancer progression and treatment.

Cited by 90 publications

References 40 publications

Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

Genome constraint through sexual reproduction: application of 4D-Genomics in reproductive biology

Evolutionary mechanism unifies the hallmarks of cancer

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