Chromosomal abnormalities involving telomeric associations (TAs) often precede replicative senescence and abnormal chromosome configurations. We report here that telomere cleavage following exposure to proapoptotic agents is an early event in apoptosis. Exposure of human and murine cancer cells to a variety of pro-apoptotic stimuli (staurosporine, thapsigargin, anti-Fas antibody, and cancer chemotherapeutic agents) resulted in telomere cleavage and aggregation, and finally their extrusion from the nuclei. Telomere loss was associated with arrest of cells in G2/M phase and preceded DNA fragmentation. Telomere erosion and subsequent large-scale chromatin cleavage were inhibited by overexpression of the anti-apoptotic protein, bcl-2, and two peptide caspase inhibitors (BACMK and zVADfmk), indicating that both events are regulated by caspase activation. The results demonstrate that telomere cleavage is an early chromatin alteration detected in various cancer cell lines leading to drug-induced apoptosis, and suggest that this event contributes to mitotic catastrophe and induction of cell death. Results also suggest that the decrease of telomeric-repeat binding factor 2 (TRF2) may be the earliest event in the ara-C-induced telomere shortening, induction of endoreduplication and chromosomal fragmentation leading to cell death.

Animals↗

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Dolastatin-10 induces polyploidy, telomeric associations and apoptosis in a murine melanoma cell line.

Our purpose was to study the effects of dolastatin-10 (Dol-10) on chromosome morphology, telomeric associations, induction of polyploidy and cell death in a metastatic murine melanoma cell line, K1735 clone X-21. Murine melanoma cells were treated with various concentrations (10 ng/ml, 100 ng/ml and 1000 ng/ml) of Dol-10 for 4, 24 and 72 h continuously and harvested immediately without recovery. In another set of experiments, cells were treated for 4 h with the same concentrations, washed with prewarmed medium and then allowed to recover in drug-free medium for 24 h and subsequently harvested. Our preliminary results indicated: i) a drug-mediated increase in the frequency of metaphases, with telomeric associations resulting in multicentric and ring configurations; ii) induction of clumping in metaphase chromosomes; iii) induction of polyploidy as a result of endoreduplication; iv) formation of micronucleated cells; and v) induction of cell death. These observations indicated that Dol-10 could be a potent antineoplastic drug against malignant melanoma. In addition to its reported interaction with cell microtubules, the mechanism of action of Dol-10 may be mediated through the loss of telomeric repeats and induction of chromosome aberrations.

Animals↗

PubMedDate not supplied

Cell-killing by paclitaxel in a metastatic murine melanoma cell line is mediated by extensive telomere erosion with no decrease in telomerase activity.

The purpose of this study was to investigate and compare the effects of paclitaxel and its water-soluble conjugates (sodium-pentetic acid-paclitaxel; polyethylene glycol-paclitaxel, and poly[L-glutamic acid]-paclitaxel) on chromosome morphology and induction of apoptosis in a metastatic murine melanoma cell line (K1735 clone X-21). For this, murine melanoma cells were treated continuously for 72 h with three concentrations (1.2 microM, 2.4 microM, and 4.8 microM) of each of paclitaxel, and conjugates. Another set of cells were pulse-treated at 2.4 microM, 4.8 microM and 9.6 microM concentrations of each of these drugs for 4 h and the recovered cells were examined after 72 h. Control cultures received only the solvents (dimethyl sulfoxide or water). Our results showed a significant increase in the frequencies of telomeric associations, chromosome aberrations, polyploidization, distorted and disintegrated chromosome morphology, and reduced telomeric signal intensity by fluorescence in situ hybridization, in treated cultures as compared to the controls. However, we detected no change in telomerase activity. In addition, the majority of interphase nuclei in treated cells showed apoptotic bodies, with chromatin condensation. These in vitro results suggest that cell death induced by paclitaxel and its water-soluble conjugates is due to the loss of telomeric repeats, as shown by reduced signal flourescence and increased telomeric associations.

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PubMedDate not supplied

Genetic alterations in human prostate cancer: a review of current literature.

We review the literature dealing with genetic alterations in human prostate cancer. We also discuss genetic predisposition and the roles of various proto-oncogenes and tumor-suppressor genes in prostate cancer initiation, progression, and metastasis. The role of telomere dynamics in prostate cancer metastasis and the induction of apoptosis is also briefly discussed.

Adenocarcinoma↗

PubMedDate not supplied

Paclitaxel and water-soluble poly (L-glutamic acid)-paclitaxel, induce direct chromosomal abnormalities and cell death in a murine metastatic melanoma cell line.

The purpose of this study was to demonstrate the effects of paclitaxel and water-soluble poly (L-glutamic acid)-paclitaxel (PG-TXL), on chromosome morphology, telomeric associations, and induction of cell death in a murine melanoma cell line (K-1735 clone X-21). Murine melanoma cells were treated with various concentrations (0.1 microgram, 1.0 microgram, 4.0 micrograms, and 8.0 micrograms/ml) of paclitaxel alone, PG alone, or PG-TXL for 2 hr and 4 hr and harvested immediately without recovery. We found that: (1) the frequency of metaphases with telomeric associations increased, (2) metaphases had clumped and distorted chromosome morphology, (3) cells accumulated in metaphase (mitotic arrest), and (4) cell death had been induced. Cells treated with PG-TXL showed more such abnormalities than did cells treated with either paclitaxel or PG alone. Our preliminary results indicate that PG-TXL may be superior to paclitaxel alone in inducing cytotoxic effects, and these effects could be mediated by various chromosomal abnormalities in cancer cells.

Animals↗