Cellular senescence and cancer treatment

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Biochimica et Biophysica Acta (BBA) – Reviews on Cancer. Volume 1775, Issue 1, January 2007, Pages 5–20

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Fig. 1. Features of cellular senescence. (A) Schematic view of a senescent cell population with characteristic morphological alterations and typical biochemical markers, including the elevated activity of β-galactosidase at an acidic pH and numerous secreted, cytoplasmic or nuclear proteins found expressed at increased levels or with a distinct pattern (e.g. heterochromatinization) in the senescent condition. (B) Drug-induced senescence-associated β-galactosidase activity visualized in a cytospin preparation of murine, Ras-driven T-cell lymphoma cells 5 days after exposure to 0.1 μg/ml adriamycin.

Cellular Senescence
Cellular senescence, an irreversible cell-cycle arrest, reflects a safeguard program that limits the proliferative capacity of the cell exposed to endogenous or exogenous stress signals. A number of recent studies have clarified that an acutely inducible form of cellular senescence may act in response to oncogenic activation as a natural barrier to interrupt tumorigenesis at a premalignant level. Paralleling the increasing insights into premature senescence as a tumor suppressor mechanism, a growing line of evidence identifies cellular senescence as a critical effector program in response to DNA damaging chemotherapeutic agents. This review discusses molecular pathways to stress-induced senescence, the interference of a terminal arrest condition with clinical outcome, and the critical overlap between premature senescence and apoptosis as both tumor suppressive and drug-responsive cellular programs.
More than 40 years ago, Hayflick and Moorhead described the observation of growth arrested human diploid cells that apparently exhausted their capacity to divide in vitro as “replicative senescence”, assuming a central role of this phenomenon in cellular and possibly organismic aging. Decades later, DNA damage signals emanating from eroded telomeres that progressively shorten every time the cell divides were unveiled as the underlying mechanism of the irreversible block in the G1-phase of the cell-cycle. Over the past several years, acutely stress-responsive forms of cellular senescence have been discovered that seem to play important roles in tumor development and treatment responses. Of note, other, not necessarily G1-restricted senescence-like forms of lasting cell-cycle blocks certainly do exist, and may reflect either a programmatic variation or an adapted response when signaling components determined to execute a “classic” G1-senescent arrest are no longer available. Based on the advanced biological characterization and the increasing mechanistic understanding, this review will mostly focus on cellular senescence that occurs in late G1 in the context of the retinoblastoma (Rb) protein restriction point.

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Fig. 4. Oncogenic provocation of failsafe responses, their mutational inactivation or regulatory suppression as the basis for malignant transformation, and the subsequent availability of these programs as drug-inducible effector mechanisms.

The understanding and utilization of cellular senescence in cancer therapy has become an emerging field of extensive research. Standard chemotherapeutic regimens are now recognized to exert their therapeutic potential not only via forcing cancer cells to die but by promoting a terminal arrest program that contributes to the outcome of cancer therapy as well. Future analyses will address whether drug-inducible senescence might even act as the essential therapeutic component in determining tumor control versus relapse particularly at the level of minimal residual disease. Importantly, little is known about the ultimate fate of senescent tumor cells in situ, and, vice versa, the immediate and long-term impact treatment-induced senescent cancer cells may have on their local environment.

At least under certain experimental conditions, acutely inducible senescence has been shown to be a formally reversible program thereby raising concerns about its lasting therapeutic impact. However, it remains to be demonstrated that a resting tumor cell in its natural environment is indeed capable of acquiring critical genetic defects in the absence of DNA synthesis. Moreover, attempts to experimentally reverse senescence entirely focus on a forced cell-cycle re-entry, often regardless of proper subsequent cell divisions, and, so far, have neglected the possibility that the regulatory chromatin-involving principles underlying cellular senescence might produce a reprogrammed phenotype that goes well beyond a terminal cell-cycle block.

The evidence that therapeutic strategies can be employed to force fully transformed cancer cells to (re-)enter the senescence program on the one side and the rapidly growing data on novel regulators of cellular senescence on the other side fuel the exciting perspective that targeted utilization of the senescence machinery may become a therapeutic option in the near future.

The efficacy of Chinese herbal medicine as an adjunctive therapy for colorectal cancer: A systematic review and meta-analysis

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Linda L.D. Zhong, Hai-Yong Chen, William C.S. Cho, et al. Complementary Therapies in Medicine, Volume 20, Issue 4, August 2012, Pages 240-252

Although Chinese herbal medicine (CHM) has been widely used as an adjunctive therapy for colorectal cancer in Asia, its efficacy is not well defined. The purpose of this systematic review is to assess the efficacy of CHM as an adjunctive therapy to chemotherapy for the patients with colorectal cancer. Randomized controlled trials with CHM to treat colorectal cancer were extensively searched in seven databases. Two researchers independently assessed the quality and validity of included trials and extracted outcome data for synthesis. 20 trials were included for analysis. Compared to using chemotherapy alone, CHM combined with chemotherapy significantly increased 1- and 3-year survival rate [odds ratio (OR) 2.41, 95% confidence interval (CI) 1.32–4.41; OR 2.40, 95% CI 1.49–3.87]. The combined therapy significantly slowed colorectal cancer progression (OR 0.50, 95% CI 0.32–0.77) and improved quality of life (OR 3.43, 95% CI 2.35–5.02). It had positive effects in immunoregulation. CHM as an adjunctive therapy also had significant advantages in reducing the adverse effects of chemotherapy. This systematic review suggests that CHM as an adjunctive therapy with chemotherapy versus chemotherapy alone has significant efficacy in terms of prolonging survival, enhancement of tumor response, improvement of quality of life, immunoregulation, and alleviation of acute adverse effects. However, a firm conclusion could not be reached because of the poor quality of the included trials. Further trials with higher quality are required and the efficacy in other forms of advantages remains to be further determined.

Guidelines for randomised controlled trials investigating Chinese herbal medicine

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herbs Andrew Flower, Claudia Witt, Jian Ping Liu, Gudrun Ulrich-Merzenich, et al. Journal of Ethnopharmacology, Volume 140, Issue 3, 10 April 2012, Pages 550–554 Ethnographic relevance Clinical trials investigating Chinese herbal medicine (CHM) have been frequently criticised for their lack of scientific rigour. As part of the GP-TCM project a team of experienced clinical researchers and CHM practitioners have developed clinical trial guidelines for CHM that combine an appreciation for traditional methods of practice with detailed and practical advice on research methodology. Materials and methods recommended first dose cialis This paper presents an executive summary of this work. It introduces the practice of CHM and the key considerations that need to be addressed whilst researching this traditional medical system. Results These guidelines emphasise the importance of identifying best practice, and then developing and applying appropriate cialis generic online and rigorous research methodologies to investigate CHM as a whole system. Conclusions It is hoped that this will encourage a thoughtful and meticulous process of investigation that will clarify the contribution that CHM can make to our future healthcare. Innovative new approaches are considered including the application of the new “omic” technologies and systems biology as a way of enhancing our understanding of traditional practice

The potential of metabolic fingerprinting as a tool for the modernisation of TCM preparations

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Helen Sheridan, Liselotte Krenn, Renwang Jiang, Ian Sutherland, et al. Journal of Ethnopharmacology, Volume 140, Issue 3, 10 April 2012, Pages 482–491 A vast majority Chinese herbal medicines (CHM) are traditionally administered as individually prepared water decoctions (tang) which are rather complicated in practice and their dry extracts show technological problems that hamper straight production of more convenient application forms. Modernised extraction procedures may overcome these difficulties but there is lack of clinical evidence supporting their therapeutic equivalence to traditional decoctions and their quality can often not solely be attributed to the single marker compounds that are usually used for chemical extract optimisation. As demonstrated by the example of the rather simple traditional TCM formula Danggui Buxue Tang, both the chemical composition and the biological activity of extracts resulting from traditional water decoction are influenced by details of the extraction procedure and especially involve pharmacokinetic synergism based on co-extraction. Hence, a more detailed knowledge about the traditional extracts’ chemical profiles and their impact on biological activity is desirable in order to allow the development of modernised extracts that factually contain the whole range of compounds relevant for the efficacy of the traditional application. We propose that these compounds can be identified by metabolomics based on comprehensive fingerprint analysis of different extracts with known biological activity. TCM offers a huge variety of traditional products of the same botanical origin but with distinct therapeutic properties, like differentially processed drugs and special daodi qualities. Through this variety, TCM gives an ideal field for the application of metabolomic techniques aiming at the identification of active constituents.

“Its main function is to produce important proteins and

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