Verapamil and Its Derivative Trigger Apoptosis through Glutathione Extrusion by Multidrug Resistance Protein MRP1

Trompier, Doriane; Chang, Xiu Bao; Barattin, Régis; d′Hardemare, Amaury du Moulinet; Pietro, Attilio Di; Baubichon‐Cortay, Hélène

doi:10.1158/0008-5472.can-04-0143

Cited by 118 publications

(136 citation statements)

References 30 publications

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“…Therefore, a subsequent increase in cellular doxorubicin concentration by indomethacin may have partly played a role. Other mechanisms by which indomethacin might induce apoptosis are increased glutathione extrusion mediated by MRP1 (Trompier et al, 2004) or increased ATP consumption by MRP1 ATPase activity in analogy to the observed verapamil-induced ATP consumption in P-glycoprotein-overexpressing cells (Broxterman et al, 1989).…”

Section: Discussionmentioning

confidence: 96%

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

et al. 2005

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Small-cell lung cancers (SCLCs) initially respond to chemotherapy but are often resistant at recurrence. A potentially new method to overcome resistance is to combine classical chemotherapeutic drugs with apoptosis induction via tumour necrosis factor (TNF) death receptor family members such as Fas. The doxorubicin-resistant human SCLC cell line GLC 4 -Adr and its parental doxorubicinsensitive line GLC 4 were used to analyse the potential of the Fas-mediated apoptotic pathway and the mitochondrial apoptotic pathway to modulate doxorubicin resistance in SCLC. Western blotting showed that all proteins necessary for death-inducing signalling complex formation and several inhibitors of apoptosis were expressed in both lines. The proapototic proteins Bid and caspase-8, however, were higher expressed in GLC 4 -Adr. In addition, GLC 4 -Adr expressed more Fas (3.1x) at the cell membrane. Both lines were resistant to anti-Fas antibody, but plus the protein synthesis inhibitor cycloheximide anti-Fas antibody induced 40% apoptosis in GLC 4 -Adr. Indomethacin, which targets the mitochondrial apoptotic pathway, induced apoptosis in GLC 4 -Adr but not in GLC 4 cells. Surprisingly, in GLC 4 -Adr indomethacin induced caspase-8 and caspase-9 activation as well as Bid cleavage, while both caspase-8 and caspase-9 specific inhibitors blocked indomethacin-induced apoptosis. In GLC 4 -Adr, doxorubicin plus indomethacin resulted in elevated caspase activity and a 2.7-fold enhanced sensitivity to doxorubicin. In contrast, no effect of indomethacin on doxorubicin sensitivity was observed in GLC 4 . Our findings show that indomethacin increases the cytotoxic activity of doxorubicin in a doxorubicin-resistant SCLC cell line partly via the death receptor apoptosis pathway, independent of Fas.

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Section: Discussionmentioning

confidence: 96%

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

et al. 2005

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“…37 Pharmacological activation of MRPs induces apoptosis by GSH depletion. 38 In clear contrast, other studies have shown that inhibition of MRPmediated transport accelerates apoptosis. 20,21 Conversely, overexpression of MRP proteins inhibit cell death induced by death receptor activation and cytotoxic drugs.…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 93%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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“…However, the calcium channel blocker verapamil and its derivative NMeOHI2, in addition to the several non-steroidal anti-inflammatory drugs (e.g., indomethacin), have shown collateral sensitivity toward MRP1 overexpressing cells [191,192] . These agents were proposed to trigger apoptosis in cells overexpressing MRP1 via intracellular GSH depletion.…”

Section: Examples Of Such Inhibitors Are Cyclosporine a [26184-187]mentioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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Verapamil and Its Derivative Trigger Apoptosis through Glutathione Extrusion by Multidrug Resistance Protein MRP1

Abstract: ABSTRACT

Cited by 118 publications

References 30 publications

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

Apoptosis and glutathione: beyond an antioxidant

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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