Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells

André, Nicolas; Carré, Manon; Brasseur, Gaël; Pourroy, Bertrand; Kovacic, Hervé; Briand, Claudette; Braguer, Diane

doi:10.1016/s0014-5793(02)03691-8

Cited by 122 publications

(83 citation statements)

References 34 publications

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“…4F). The actions of Taxol on mitochondria were recently described in non-excitable cells (14,15 (45). However, these effects can be explained as the modulation of the ER (not the mitochondrial) function by MT.…”

Section: Microtubules and Ca 2ϩ Signaling Between Mitochondria And Ermentioning

confidence: 99%

“…Only one intracellular target has been established for Taxol thus far; it binds to a site located on the inner surface of the MT wall (12) and enhances lateral contacts between tubulin dimers (13). Recent evidence obtained in non-neuronal cells (14,15) suggests that Taxol can directly target tubulin bound to mitochondria. We show here that Taxol and nocodazole depolarized mitochondria and released previously stored Ca 2ϩ in brain stem pre-Bötzinger complex neurons.…”

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confidence: 99%

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[Ca2+] Signaling between Mitochondria and Endoplasmic Reticulum in Neurons Is Regulated by Microtubules

Mironov

Ivannikov

Johansson

2005

Journal of Biological Chemistry

142

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The positioning and dynamics of organelles depend on membrane-cytoskeleton interactions. Mitochondria relocate along microtubules (MT), but it is not clear whether MT have direct effects on mitochondrial function. Using two-photon microscopy and the mitochondrial fluorescent dyes rhodamine 123 and Rhod-2, we showed that Taxol and nocodazole, which correspondingly stabilize and disrupt MT Interactions between intracellular membranes and microtubules (MT) 1 determine the structure and positioning of subcellular organelles and direct their dynamic movements. MT can associate with the organelles either dynamically or in a stable fashion. Dynamic interactions are required for organelle traffic and involve microtubule motors such as kinesin and dynein (1, 2). Stable interactions are responsible for the positioning and structural maintenance of the endoplasmic reticulum (ER) (3), and mitochondria (4 -9). However, it is not known whether MT can influence the function of mitochondria and ER. Taxol (paclitaxel) and nocodazole, which correspondingly stabilize and disrupt MT, change the structure of the cytoskeleton. In proliferating cells, these drugs prevent normal mitotic spindle formation and cause the cells to halt mitosis and to initiate apoptosis. In comparison with MT-disrupting drugs, Taxol is less toxic and has recently been promoted for the treatment of ovarian, breast, lung, and prostate cancers (10), but it is often accompanied by serious peripheral neuropathies (11), the origin and mechanisms of which are yet unclear. Only one intracellular target has been established for Taxol thus far; it binds to a site located on the inner surface of the MT wall (12) and enhances lateral contacts between tubulin dimers (13). Recent evidence obtained in non-neuronal cells (14, 15) suggests that Taxol can directly target tubulin bound to mitochondria. We show here that Taxol and nocodazole depolarized mitochondria and released previously stored Ca 2ϩ in brain stem pre-Bötzinger complex neurons. Both effects were inhibited by cyclosporin A (CsA) and 2-aminoethoxydiphenyl borate (APB), commonly used blockers of mitochondrial permeability transition pore (mPTP). mPTP opening was validated by using the mPTP-specific calcein/Co 2ϩ imaging technique (16). The effects of Taxol were not mediated by enhanced Ca 2ϩ influx, leading to subsequent overload of mitochondria with Ca 2ϩ or overproduction of reactive oxygen species (ROS), the two main factors that can promote the opening of mPTP with subsequent initiation of apoptosis (17-19). Electron and optical microscopy revealed close interactions of MT with mitochondria in living neurons and isolated mitochondria. We therefore suggest that mPTP induction is triggered by modification of MT interactions with proteins of the outer mitochondrial membrane, e.g. the voltagedependent anion channel (VDAC) (9, 20 -23). In non-neuronal cells mitochondria and ER are closely opposed, and mitochondria can capture Ca 2ϩ released from the ER (21, 24). In neurons, the positions of mitochondria and ER a...

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Section: Microtubules and Ca 2ϩ Signaling Between Mitochondria And Ermentioning

confidence: 99%

mentioning

confidence: 99%

[Ca2+] Signaling between Mitochondria and Endoplasmic Reticulum in Neurons Is Regulated by Microtubules

Mironov

Ivannikov

Johansson

2005

Journal of Biological Chemistry

142

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“…It is licensed in many countries as an agent for reversing the effect of drugs and poisons causing the anticholinergic syndrome. In the present work, we show the effect of this natural compound in a model of peripheral neuropathy, a syndrome characterized by nerve damage and nervous tissue degeneration, and the role of apoptosis in tissue alterations and cell loss is widely substantiated (Dalakas et al, 2001;Andre et al, 2002;Moulder et al, 2002;Siler-Marsiglio et al, 2004;Leinninger et al, 2006;Melli et al, 2006;Di Cesare Mannelli et al, 2007).…”

Section: Discussionmentioning

confidence: 75%

“…Mitochondrial membrane permeabilization causes release of cytochrome C and the subsequent formation of a complex that initiates cleavage and activation of caspases (Dalakas et al, 2001;Andre et al, 2002;Moulder et al, 2002;Siler-Marsiglio et al, 2004;Leinninger et al, 2006;Melli et al, 2006).…”

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confidence: 99%

Neuropathy‐induced apoptosis: Protective effect of physostigmine

Mannelli

Bartolini

Ghelardini

2009

J of Neuroscience Research

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Traumatic, infectious, metabolic, and chemical noxa to the nervous system are the etiology of a crippling disease generally termed neuropathy. Motor disorders, altered sensibility, and pain are the pathognomonic traits. Cellular alterations induced by this chronic pathology include mitochondrial dysfunctions that lead to the activation of the apoptotic cascade. Energy imbalance can compromise the maintenance of mitochondrial membrane potential, furthering the release of cytochrome C and the subsequent cleavage and activation of caspases. Chronic constriction injury (CCI) of the rat sciatic nerve is a neuropathy model able to induce a strong mitochondrial impairment with a consequent apoptotic induction. In this model, the acetylcholinesterase inhibitor physostigmine is administered at 0.125 mg/kg i.p. (twice per day) starting from the operation and for 15 days after. The cholinergic activation reduces cytosolic levels of cytochrome C, suggesting an improved stability of the mitochondrial membrane, and the expression level of the active caspase 3 fragments (19, 16 kDa) is reduced significantly with respect to saline treatment. Accordingly, physostigmine impairs caspase 3 protease activity. In fact, the target of the activated caspase 3, the 89-kDa PARP fragment, is significantly less expressed in the ligated nerve of physostigmine-treated rats, reaching levels that are comparable to those in the contralateral unligated nerve. Finally, this natural acetylcholinesterase inhibitor reduces DNA fragmentation both in the proximal and in the distal parts of the nerve. This protection correlates with the induction of XIAP. Therefore, apoptosis, central to tissue degeneration, is prevented by repeated physostigmine treatment of CCI animals. V V C 2009 Wiley-Liss, Inc.

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“…5 By opening the mitochondrial PTP, there is a reduction in mitochondrial membrane potential and Ca 2+ release from mitochondria, leading to calcium loss, which indicates that some of the acute adverse effects of anti cancer drugs could be due to their effect on mitochondrial function.…”

Section: Paclitaxelmentioning

confidence: 99%

Drugs acting on mitochondrial pathways

Srinivasan

Selvarajan

Dkhar

et al. 2017

Int J Basic Clin Pharmacol

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Mitochondrion, “the power house” of the cell plays a vital role in generating energy for the intricate functions of the cells. Mitochondria also play important roles in various apoptotic pathways. Around 80-90% of the ATP generated in cells is contributed by these organelles through the process of oxidative phosphorylation. Though this process is essential for the functioning of cells it also generates various Reactive Oxygen Species (ROS), which are toxic to cells. Hence mitochondrial dysfunction is hypothesized to be an important factor in the occurrence of disorders related to aging such as neurodegeneration and malignancies. Several commonly used drugs in clinical practice exert their action by interacting with mitochondrial pathways. This review attempts to focus on the various groups of drugs which act on mitochondria and are utilized for therapy of conditions like cancer, diabetes mellitus, neurodegeneration and so on.

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Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells

Cited by 122 publications

References 34 publications

[Ca2+] Signaling between Mitochondria and Endoplasmic Reticulum in Neurons Is Regulated by Microtubules

[Ca2+] Signaling between Mitochondria and Endoplasmic Reticulum in Neurons Is Regulated by Microtubules

Neuropathy‐induced apoptosis: Protective effect of physostigmine

Drugs acting on mitochondrial pathways

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