Co-ordinated over-expression of the MRP and γ-glutamylcysteine synthetase genes, but not MRD1, correlates with doxorubicin resistance in human malignant mesothelioma cell lines

Öğretmen, Besim; Bahadori, Hamid R.; McCauley, Mary D.; Boylan, A; Green, Mark R.; Safa, Ahmad R.

doi:10.1002/(sici)1097-0215(19980302)75:5<757::aid-ijc15>3.0.co;2-3

Cited by 34 publications

(17 citation statements)

References 18 publications

(23 reference statements)

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“…at ASPET Journals on May 10, 2018 jpet.aspetjournals.org sufficient to explain all mechanisms responsible for multidrug resistance (Ogretmen et al, 1998;Soini et al, 2001). Preliminary experiments using specific antibody to multidrug resistance protein 1 revealed that 0 cells used in the present experiments did not express this protein (data not shown).…”

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confidence: 65%

Mitochondria Determine the Efficacy of Anticancer Agents that Interact with DNA but Not the Cytoskeleton

Hara¹,

Kasahara²,

Takahashi³

et al. 2011

J Pharmacol Exp Ther

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Although chemotherapy is an important method for the treatment of patients with cancer, its efficacy is limited because of different sensitivities of tumor cells to anticancer agents and/or side effects on normal tissues. The present work demonstrates that mitochondria play a crucial role in the apoptosis of cancer cells induced by anticancer agents that interact with DNA but not with the cytoskeleton. Agents that interact with DNA selectively enhanced generation of reactive oxygen species (ROS) in mitochondria, released cytochrome c, and activated caspase-9 and caspase-3 to induce apoptosis of mesothelioma H2052 cells but not their 0 cells, which lack mitochondrial DNA (mtDNA). The sensitivity of a variety of cells to the agents showed positive correlation with the amounts of their mitochondria. In contrast, agents that selectively affect the cytoskeleton activated caspase-8 and caspase-3 and equally induced apoptosis of both H2052 and their 0 cells by a mitochondria-independent mechanism. The results suggest that mtDNA is a potential target for the anticancer agents that interact with DNA to induce ROS-dependent apoptosis of cancer cells, whereas agents that affect the cytoskeleton induce cell death by a mitochondria-and ROS-independent mechanism. The present observation is important for the selection of medicine for chemotherapy of patients with cancer.

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confidence: 65%

Mitochondria Determine the Efficacy of Anticancer Agents that Interact with DNA but Not the Cytoskeleton

Hara¹,

Kasahara²,

Takahashi³

et al. 2011

J Pharmacol Exp Ther

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“…Previous work has shown that an association exists between a coordinated increase in the expression of antioxidant proteins and resistance to anticancer drugs. For example, high levels of GCLC and MRP have reported to be associated with increased resistance towards doxorubicin in mesothelioma cells (49), and an increase in GCLC has been associated with resistance to cisplatin in ovarian cells (50). Recently, it has been reported that acquired resistance of KCL22 human chronic myelogenous leukemia cells to imatinib was linked to increases in both GSH levels and the amounts of nuclear Nrf2 (51).…”

Section: Discussionmentioning

confidence: 99%

Generation of a Stable Antioxidant Response Element–Driven Reporter Gene Cell Line and Its Use to Show Redox-Dependent Activation of Nrf2 by Cancer Chemotherapeutic Agents

2006

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The NF-E2 p45-related factor 2 (Nrf2) regulates cytoprotective genes that contain an antioxidant response element (ARE) in their promoters. To investigate whether anticancer drugs can induce ARE-driven gene expression, we have developed a stable human mammary MCF7-derived reporter cell line called AREc32, which contains a luciferase gene construct controlled by eight copies of the cis-element. In these cells, luciferase activity was increased up to 50-fold following treatment with 50 Mmol/L tert-butylhydroquinone (t-BHQ). Basal and inducible luciferase activities in AREc32 cells were increased by forced overexpression of Nrf2 and reduced by knockdown of endogenous Nrf2 expression with RNA interference. Depletion of cellular reduced glutathione (GSH) by treatment of AREc32 cells with L-buthionine-S,R -sulfoximine (BSO) did not influence basal levels of luciferase activity, but pretreatment with BSO augmented induction of luciferase activity by t-BHQ. Induction of reporter activity by t-BHQ in AREc32 cells was suppressed markedly by the antioxidants N-acetylcysteine and GSH but only modestly by vitamins C or E, suggesting that ARE-luciferase expression is induced primarily by thiol-active electrophiles rather than free radicals. The anticancer drugs cisplatin, etoposide, mitoxantrone, chlorambucil, melphalan, and carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU)] weakly induced luciferase activity in AREc32 cells. Moreover, treatment of AREc32 cells with BSO immediately before exposure to anticancer drugs enhanced induction of ARE-driven luciferase activity by cisplatin, BCNU, chlorambucil, and melphalan and also induced endogenous AKR1C (AKR1C refers to AKR1C1 and AKR1C2), a target gene of Nrf2. Our findings show that Nrf2 can be activated by certain anticancer agents, and this will influence the effectiveness of chemotherapy. (Cancer Res 2006; 66(22): 10983-94)

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“…3 HMM is considered an intrinsically resistant tumor, 4 but no general agreement exists about the molecular mechanisms: MDR in this tumor has been attributed to overexpression of ABC transporters [4][5][6] and g-glutamylcysteine synthetase 39 or to other mechanisms. 40,41 ABC transporters, such as Pgp, MRP1 and MRP2, [4][5][6] actively extrude several anticancer drugs, including doxorubicin, which has been one of the chemotherapeutic agents most used in HMM therapy. 3,4 Thus, both single agent and combinatory therapy obtain a successful response in not more than 20% of patients.…”

Section: Discussionmentioning

confidence: 99%

“…40,41 ABC transporters, such as Pgp, MRP1 and MRP2, [4][5][6] actively extrude several anticancer drugs, including doxorubicin, which has been one of the chemotherapeutic agents most used in HMM therapy. 3,4 Thus, both single agent and combinatory therapy obtain a successful response in not more than 20% of patients. 3,38,42 We have previously shown that doxorubicin-sensitive and doxorubicin-resistant human colon cancer cells exhibit a different capacity to produce NO 16 and that doxorubicin resistance is reverted by inducers of NO production, such as cytokines and atorvastatin, or NO donors.…”

Section: Discussionmentioning

confidence: 99%

Statins revert doxorubicin resistance via nitric oxide in malignant mesothelioma

Riganti

Orecchia

Pescarmona

et al. 2006

Intl Journal of Cancer

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Human malignant mesothelioma (HMM) is resistant to many anticancer drugs, including doxorubicin. Mevastatin and simvastatin, 2 inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, potentiated the intracellular accumulation and the cytotoxicity of doxorubicin in HMM cells constitutively expressing Pglycoprotein and multidrug resistance-associated protein 3. This effect of statins was nitric oxide (NO)-dependent, since it was reverted by either an NO synthase inhibitor or an NO scavenging system. The NO synthase up-regulation in HMM and other cells is known to be associated with the activation of the transcription factor NF-jB: in HMM cells statins increased the NF-jB translocation into the nucleus, decreased the level of the NF-jB inhibitor IkBa and increased the phosphorylation/activation of IkB kinase a (IKKa). IKKa is under the negative control exerted by RhoA in its prenylated (active) form: incubation of HMM cells with statins lowered the amount of active RhoA and the level of Rho-associated kinase activity. All statins' effects were reverted by mevalonic acid, thus suggesting that they were mediated by the inhibition of HMGCoA reductase and were likely to be subsequent to the reduced availability of precursor molecules for RhoA prenylation. Both the Rho kinase inhibitor Y27632 and the RhoA inhibitor toxin B (from Clostridium difficile) mimicked the statins' effects, enhancing doxorubicin accumulation, NO synthesis and IKKa phosphorylation and decreasing the amount of IkBa in HMM cells. Simvastatin, Y27632 and toxin B elicited tyrosine nitration in the P-glycoprotein, thus providing a likely mechanism by which NO reverts the doxorubicin resistance in HMM cells. ' 2006 Wiley-Liss, Inc.

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Co-ordinated over-expression of the MRP and γ-glutamylcysteine synthetase genes, but not MRD1, correlates with doxorubicin resistance in human malignant mesothelioma cell lines

Cited by 34 publications

References 18 publications

Mitochondria Determine the Efficacy of Anticancer Agents that Interact with DNA but Not the Cytoskeleton

Mitochondria Determine the Efficacy of Anticancer Agents that Interact with DNA but Not the Cytoskeleton

Generation of a Stable Antioxidant Response Element–Driven Reporter Gene Cell Line and Its Use to Show Redox-Dependent Activation of Nrf2 by Cancer Chemotherapeutic Agents

Statins revert doxorubicin resistance via nitric oxide in malignant mesothelioma

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