Potentiation of Bleomycin Lethality by Anticalmodulin Drugs: A Role for Calmodulin in DNA Repair

Chafouleas, James G.; Bolton, Wade E.; Means, Anthony R.

doi:10.1126/science.6203171

Cited by 94 publications

(40 citation statements)

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“…We found that HT treatment (even for non-toxic exposures of 30min at 44°C) restricts the access of active drug to DNA. This observation is consistent with the notion that an increase in nuclear protein in HT-treated cells reduces the accessibility of DNA (Roti Roti, 1982) and the observation (Braun & Hahn, 1975) Chafouleas et al, 1984) after BLM removal would only monitor effects on a restricted class of lesions. Consequently we have adopted the approach that changes in the levels of BLM-induced DNA damage for simultaneous exposures to HT and TFP, effectively monitor the capacity of rapair processes to limit lesion accumulation.…”

Section: Discussionsupporting

confidence: 78%

“…Calmodulin is a relatively low molecular mass, acidic calcium binding protein which is uniquitous amongst eukaryotic cells. Apart from its apparent importance in the control of cell proliferation (for review see Means et al, 1982) there is recent evidence that calmodulin may have a role in DNA repair given the capacity of calmodulin inhibitors to inhibit the repair of bleomycin induced DNA ©) The Macmillan Press Ltd., 1986 damage (Chafouleas et al, 1984) and UV-induced pyrimidine dimers (Charp & Regan, 1985).…”

mentioning

confidence: 99%

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Interaction of bleomycin, hyperthermia and a calmodulin inhibitor (trifluoperazine) in mouse tumour cells: Ii. DNA damage, repair and chromatin changes

Smith¹,

Mircheva²,

Bleehen³

1986

Br J Cancer

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Summary We have reported in the preceding paper that the treatment of plateau phase mouse EMT6 tumour cells with a combination of hyperthermia (HT; 44°C) and trifluoperazine (TFP; 30, an inhibitor of calmodulin) greatly enhances the cytotoxicity of the antitumour drug belomycin (BLM). The cytotoxic action of BLM is thought to arise from the induction of DNA damage in a manner which reflects chromatin accessibility. Thus we have studied the effects of the two modifiers (HT and TFP) on chromatin structure and BLM-induced DNA damage. Co-treatment of cells with HT and TFP altered chromatin organisation by the formation and slow resolution of new DNA attachment sites at the nuclear matrix. HT increased drug-induced DNA damage (strand breaks and alkali-labile lesions) by the general depression of repair rather than through the generation of new sites for drug action. TFP produced a more discrete block in the repair of alkali-labile lesions in DNA. Both processes appear to occur for the combination of BLM, HT and TFP, and we propose that the novel chromatin configuration permits the accumulation of potentially lethal DNA strand breaks. Our study indicates the potential value of chromatin/DNA repair modifying regimens for overcoming the poor responsiveness of some tumour cells to chemotherapeutic drugs and provides a rational basis for the use of calmodulin inhibitors in thermochemotherapy.The anti-tumour glycopeptidic bleomycins are thought to exert their cytotoxic effects by damaging cellular DNA. A number of molecular mechanisms have been proposed (for review see Hecht, 1979) to explain the ability of bleomycin (BLM) to induce the liberation of free bases and the formation of single-and double-strand breaks. A central feature of recent models is the capacity of the antibiotic both to associate with DNA and to complex with ferrous iron. The ferrous oxidase activity of this complex reduces molecular oxygen to the superoxide radical, hydrogen peroxide and the potentially damaging hydroxyl radical (Caspary et al., 1982).In isolated DNA, BLM has been shown to induce single-strand breaks, alkali-labile sites (representing sites of base loss without cleavage of the phosphodiester bond) and double-strand breaks in the proportion of 5:5:1 (Lloyd et al., 1978). However, various problems are encountered in interpreting the significance of bleomycin-induced DNA damage in intact eukaryotic cells. For example, residual bleomycin may interact with DNA during the preparation of cells for damage analysis (Cox et al., 1974) and the fact that the Correspondence: P.J. Smith.

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

Interaction of bleomycin, hyperthermia and a calmodulin inhibitor (trifluoperazine) in mouse tumour cells: Ii. DNA damage, repair and chromatin changes

Smith¹,

Mircheva²,

Bleehen³

1986

Br J Cancer

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“…An important factor that governs tumor cell responsiveness to bleomycin is the cellular DNA DSB repair capacity, and, in line with this, increased sensitivity to bleomycin is observed in cells deficient in NHEJ (15,23,24). TFP, a phenothiazine class antipsychotic drug, has been reported to enhance bleomycin-induced cytotoxicity by a poorly characterized mechanism (2,4,5,22). We have previously shown that TFP can inhibit the kinase activity of the NHEJ core component DNA-PK in vitro (17).…”

Section: Discussionmentioning

confidence: 97%

“…Phenothiazines are well-characterized calmodulin antagonists (26,27), and this led Chafouleas et al (2) to propose that TFP might augment bleomycin cytotoxicity by inhibiting a putative calmodulin-regulated DNA repair pathway. Recent studies have shown that inositol phosphates serve as cofactors for DNA-PK cs during NHEJ (28 -30).…”

Section: Discussionmentioning

confidence: 99%

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

Polischouk¹,

Holgersson²,

Zong³

et al. 2007

Molecular Cancer Therapeutics

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Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non -small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycininduced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJmediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. [Mol Cancer Ther 2007;6(8):2303 -9]

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“…Among its many functions, CaM has been shown to be involved in cell proliferation [2], DNA repair [3] and gene expression [4]. In addition, CaM binds to several nuclear proteins [5].…”

Section: Introductionmentioning

confidence: 99%

Characterization of an intronless human calmodulin‐like pseudogene

Koller

Strehler

1988

FEBS Letters

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We report the isolation and characterization of a human genomic clone encoding a calmodulin-like psbudogene. It contains an open reading frame of 444 nucleotides, not interrupted by introns. The nucleotide sequence of the open reading frame shows 80%, 71% and 69% identity to the previously reported human calmodulin cDNAs kht6 [17], hCWP [22], and lhCE1 [23], respectively. The derived amino acid sequence has only 85% identity to vertebrate calmodulin, but shows four potentially functional Caz+-binding loops. In the human tissues tested, this pseudogene is not expressed, though gene structure including promoter elements and a putative polyadenylation site seems to be intact.

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Potentiation of Bleomycin Lethality by Anticalmodulin Drugs: A Role for Calmodulin in DNA Repair

Cited by 94 publications

References 14 publications

Interaction of bleomycin, hyperthermia and a calmodulin inhibitor (trifluoperazine) in mouse tumour cells: Ii. DNA damage, repair and chromatin changes

Interaction of bleomycin, hyperthermia and a calmodulin inhibitor (trifluoperazine) in mouse tumour cells: Ii. DNA damage, repair and chromatin changes

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

Characterization of an intronless human calmodulin‐like pseudogene

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