Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitrostudy

Kuranaga, Noritsugu; Shinomiya, Nariyoshi; Mochizuki, Hidetaka

doi:10.1186/1471-2407-1-10

Cited by 33 publications

(43 citation statements)

References 20 publications

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“…11 Previous studies of radiation-and genotoxic drug-induced telomerase upregulation did not detect telomere shortening in treated cells. 11,22,31,32 Similarly, in vivo etoposide treatment does not appear to alter the telomere length of HeLa cells, although etoposide treatment mediates in vitro cleavage of telomeric DNA. 46 It remains possible that telomerase upregulation could be mediated by small changes in telomere length undetectable by TRF analysis, or by other forms of DNA or telomeric damage.…”

Section: Discussionmentioning

confidence: 99%

“…One recent study reports that hTERT expression in telomerase-negative cells decreases their sensitivity to topoisomerase inhibitors such as etoposide, 9 and long-term cultivation of colorectal carcinoma cells with the genotoxic drugs cisplatin and 5-fluorouracil results in gradual lengthening of telomeres and enhanced drug resistance. 22 A clinical study of chemotherapy and epithelial ovarian cancer reports no increase in telomerase activity in cancer cells from treatment responders, whereas cancer cells from 58.3% of treatment nonresponders show an increase in telomerase activity after treatment. 47 In addition, repeated exposure of the epidermis of hairless mice to DNA-damaging UV irradiation elicits a progressive increase in telomerase activity that culminates in a 45-fold enhancement of activity in carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…16,21 Additionally, long-term exposure of colorectal carcinoma cells to cisplatin results in increased telomerase activity, telomere length and drug resistance. 22 Cisplatin's influence on telomerase activity in human cells has been studied more extensively than the effect of other chemotherapeutic drugs. Its apparent dose-dependent effect on telomerase warrants the examination of telomerase activity levels in different cell types subjected to other drug treatments.…”

Section: Introductionmentioning

confidence: 99%

“…Other therapeutic regimens reported to elicit telomerase upregulation in treated cells include the DNA-damaging agents bleomycin, 5-fluorouracil and etoposide, 16,[22][23][24][25] and various kinds of radiation. [26][27][28][29][30][31][32][33][34] Telomerase-negative mice with short telomeres are more sensitive to ionizing radiation than their telomerase-positive counterparts, and their cells sustain increased chromosomal damage and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Rapid upregulation of telomerase activity in human leukemia HL-60 cells treated with clinical doses of the DNA-damaging drug etoposide

2002

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The enzyme telomerase is implicated in cellular resistance to apoptosis, but the mechanism for this resistance remains to be elucidated. The ability of telomerase to synthesize new DNA at telomeres suggests that this enzyme might function in the repair of double-stranded DNA breaks. To distinguish the effects of double-stranded DNA break damage and apoptosis on human telomerase activity, we treated the HL-60 human hematopoietic cancer cell line with clinical doses of the chemotherapeutic drug etoposide (0.5 to 5 M), which allowed us to distinguish between events associated with DNA damageinduced cell cycle arrest, and events associated with apoptosis. Large (three-to seven-fold) upregulation of telomerase activity occurred soon after etoposide treatment (3 h) in S/G2/M-arresting populations; this upregulation was abolished at onset of apoptotic cell death. No upregulation of telomerase activity was observed in cells treated with a larger dose of etoposide (5 M) that caused cells to undergo rapid apoptosis without intervening cell cycle arrests. These observations are consistent with a possible role for telomerase upregulation during the DNA damage response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rapid upregulation of telomerase activity in human leukemia HL-60 cells treated with clinical doses of the DNA-damaging drug etoposide

2002

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“…Chemotherapeutic drugs have complex effects on telomerase activity and these complex effects are cell typedependent (14)(15)(16)(17)(18)(19). Cisplatin is a DNA cross-linking agent used in the treatment of various tumors including hepatocellular carcinoma (20,21).…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells

Guo

Ma²,

Zhou³

et al. 2009

Oncol Rep

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Abstract. The telomerase is specifically activated in most malignant tumors but is usually inactive in normal somatic cells. It has been reported that telomerase has an anti-apoptotic role and up-regulation of telomerase helps cancer cells to be resistant to chemotherapeutic agent-induced cell death. The effect of cisplatin on telomerase activity is complex, and the exact mechanism remains largely unknown. In this study, we found that cisplatin activated telomerase activity and human telomerase reverse transcriptase (hTERT) expression in SMMC7721 human hepatocellular carcinoma cell line. Lowdose cisplatin up-regulated hTERT and NF-κB p65 expression and increased telomerase and NF-κB activity. Inhibition of NF-κB attenuated the hTERT expression and telomerase activity exposed to cisplatin, suggesting that NF-κB is responsible for the cisplatin-induced activation of the hTERT. Furthermore, preincubation of low-dose cisplatin which induced high expression of hTERT help hepatocellular carcinoma SMMC7721 cells survive under the high concentration of anti-cancer drugs. Inhibition of hTERT increased sensitivity of SMMC7721 cells to chemotherapy. Taken together, these results suggested that up-regulation of hTERT expression by low-dose cisplatin is NF-κB-dependent and contributes to chemotherapy resistance in human hepatocellular cancer cells. IntroductionTelomerase is a cellular reverse transcriptase that catalyses the synthesis and extension of telomeric DNA (1,2). This enzyme is specifically activated in most malignant tumors but is usually inactive in normal somatic cells (3,4). The catalytic core of human telomerase is composed of an RNA subunit known as hTER (human telomerase RNA) and a protein subunit named as hTERT (human telomerase reverse transcriptase). Although the RNA subunit (hTR) of the human telomerase complex is constitutively expressed in both tumor and normal somatic tissues, expression of the catalytic subunit (hTERT) correlates with telomerase activity and is a key step of activation of telomerase (5-7). Substantial experiments demonstrate that the transcriptional regulation of hTERT expression represents the primary and rate-limiting step in the activation of telomerase activity in most cells (8)(9)(10)(11). Several studies have indicated that hTERT has an anti-apoptotic activity in addition to its role in telomere length maintenance (12,13).Chemotherapeutic drugs have complex effects on telomerase activity and these complex effects are cell typedependent (14-19). Cisplatin is a DNA cross-linking agent used in the treatment of various tumors including hepatocellular carcinoma (20,21). Human testicular cancer cells treated with lethal doses of cisplatin exhibit decreased telomerase activity (22). In leukemic cells, telomerase activity was also downregulated after treatment with cisplatin (23). Additionally, long-term exposure of colorectal carcinoma cells to cisplatin results in increased telomerase activity (18). However, the exact mechanism of the complex effect of cisplatin on telomerase activity...

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Tumour‐cell apoptosis after cisplat in treatment is not telomere dependent

Jeyapalan

Saretzki

Leake

et al. 2006

Intl Journal of Cancer

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Cisplatin is a major chemotherapeutic agent, especially for the treatment of neuroblastoma. Telomeres with their sequence (TTAGGG) n are probable targets for cisplatin intrastrand crosslinking, but the role of telomeres in mediating cisplatin cytotoxicity is not clear. After exposure to cisplatin as single dose or continuous treatment, we found no loss of telomeres in either SHSY5Y neuroblastoma cells (telomere length, 4 kbp), HeLa 229 cells (telomere length, 20 kbp) or in the acute lymphoblastic T cell line 1301 (telomere length, 80 kbp). There was no induction of telomeric single strand breaks, telomeric overhangs were not degraded and telomerase activity was down-regulated only after massive onset of apoptosis. In contrast, cisplatin induced a delayed formation of DNA strand breaks and induced DNA damage foci containing c-H2A.X at nontelomeric sites. Interstitial DNA damage appears to be more important than telomere loss or telomeric damage as inducer of the signal pathway towards apoptosis and/or growth arrest in cisplatin-treated tumour cells. ' 2005 Wiley-Liss, Inc.Key words: telomeres; telomerase; cisplatin; neuroblastoma; apoptosis; DNA damage Cisplatin is a chemotherapeutic agent for the treatment of neuroblastoma, a common solid extracranial malignancy of childhood and infancy. Cisplatin binds to DNA to cause a biological effect by forming cisplatin-DNA adducts and is a potent inducer of apoptosis.1,2 The major DNA adduct formed is the bifunctional intrastrand cross-link between adjacent guanines. It is unclear how the cisplatin-DNA adducts induce cytotoxicty, though this is widely attributed to the formation of various types of cross-links, especially intrastrand cross-links, 3 which are by far the most frequent lesions, 4 although interstrand cross-links might be more cytotoxic. 5Telomeres, the DNA-protein structures that form the ends of chromosomes, play an important role for the stability of the genome. Their shortening with each round of DNA replication is caused by different mechanisms, one of these being their sensitivity to DNA damage. 6 Cisplatin has been shown to bind preferentially to runs of 2 or more consecutive guanines.7 Human telomeric DNA contains triple runs of guanines at high density, therefore cisplatin may preferentially target telomeric DNA. Telomeres end in single stranded overhangs of the G-rich strand, which appear to be essential for telomeric higher order structure 8 and for the generation of DNA damage signals from telomeres.9-11 Telomerase, a reverse transcriptase that uses an RNA template to add telomeric repeats onto the ends of chromosomes, 12,13 is expressed in 94% of neuroblastomas 14 and has been shown to be a powerful independent prognostic factor.15 Thus a specific role of the telomere/telomerase complex in mediating cisplatin-induced neuroblastoma cell death may be expected and has been more or less directly indicated by some data, [16][17][18][19][20][21][22] but refuted by others. 23-25Given these contradictory results, we decided to examine whether there is a...

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Long-term cultivation of colorectal carcinoma cells with anti-cancer drugs induces drug resistance and telomere elongation: an in vitrostudy

Cited by 33 publications

References 20 publications

Rapid upregulation of telomerase activity in human leukemia HL-60 cells treated with clinical doses of the DNA-damaging drug etoposide

Rapid upregulation of telomerase activity in human leukemia HL-60 cells treated with clinical doses of the DNA-damaging drug etoposide

Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells

Tumour‐cell apoptosis after cisplat in treatment is not telomere dependent

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