cis-Diamminedichloroplatinum (II) (cisplatin) alters microtubule assembly dynamics

Boekelheide, Kim; Arcila, Maria E.; Eveleth, Julia

doi:10.1016/0041-008x(92)90156-m

Cited by 34 publications

(20 citation statements)

References 41 publications

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“…However, chloride concentration in most cells is very low (in some cases essentially zero), and once cisplatin enters the cell, the low chloride environment facilitates formation of the highly reactive monoaquocisplatin (1). Several groups have reported that extended exposure of MTP to platinum compounds results in the loss of the ability of MTP to polymerize into microtubules, a phenomenon called decay (21)(22)(23). Consistent with these reports, we observed that when monoaquocisplatin was incubated with MTP before initiation of MTP polymerization assays, with increasing incubation time, there was increased protein denaturation/precipitation.…”

Section: Effect Of Extended Exposure To Monoaquocisplatin On Mtp Polysupporting

confidence: 79%

“…3B) would not be reactive with these moieties on tubulin or MAPs. Cisplatin interactions with MTP are not thought to contribute to its antitumor effects but may be one contributing mechanism behind cisplatin-induced neurotoxicity (6,(21)(22)(23)(24). Mesna, a metabolite of BNP7787, was able to protect against monoaquocisplatin-induced perturbation of MTP polymerization, and we propose that, in vivo, at specific locations BNP7787 may undergo reduction to mesna (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike paclitaxel, cisplatin interactions with MTP are not thought to be important for its antitumor activity. However, interactions between cisplatin and MTP have been reported (21)(22)(23)(24), and these interactions might adversely affect the structural integrity of axons and impair axonal transport, thereby contributing to peripheral neuropathy accompanying cisplatin chemotherapy (6,19,20,35).…”

Section: Introductionmentioning

confidence: 99%

“…The antitumor effect of taxanes are due to altered cytoskeletal microtubule protein (MTP) functioning that can result in activation of apoptotic pathways, whereas taxane-induced CIPN is believed to be a consequence of damage to nerves that are rich in MTP (4)(5)(6)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Paclitaxel (Fig.…”

Section: Introductionmentioning

confidence: 99%

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BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro

Parker

Petluru

et al. 2010

Molecular Cancer Therapeutics

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Taxane and platinum drugs are important agents in the treatment of cancer and have shown activity against a variety of tumors, including ovarian, breast, and lung cancer, either as single agents or in combination with other chemotherapy drugs. However, a serious and prevalent side effect of taxane (docetaxel and all formulations/derivatives of paclitaxel) and platinum (cisplatin, carboplatin, and oxaliplatin) agents is dose-limiting chemotherapy-induced peripheral neuropathy (CIPN). CIPN can result in treatment delays, dose modifications, and, in severe cases, discontinuation of chemotherapy. Consequently, effective treatments for CIPN are needed. Dimesna (BNP7787; Tavocept TM ; disodium 2,2′-dithio-bis-ethanesulfonate) is an investigational drug that is undergoing international clinical development as a treatment that is coadministered with first-line taxane and platinum combination chemotherapy in patients with inoperable advanced primary adenocarcinoma of the lung. BNP7787 is currently being developed with the objective of increasing the survival of cancer patients receiving taxane-and/or cisplatin-based chemotherapy. Additional data indicate that BNP7787 may also protect against common and serious chemotherapy-induced toxicities, including chemotherapy-induced anemia, nausea, emesis, nephrotoxicity, and neuropathy, without interfering with antitumor activity of the chemotherapeutic agent(s). Studies herein show that BNP7787 prevents aberrant microtubule protein (MTP) polymerization that is caused by exposure of MTP to paclitaxel or cisplatin. BNP7787 modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of BNP7787, protects against time-dependent cisplatin-induced inactivation of MTP. We propose that interactions between BNP7787 and MTP may play a role in BNP7787-mediated protection against CIPN.Mol Cancer Ther; 9(9); 2558-67. ©2010 AACR.

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Section: Effect Of Extended Exposure To Monoaquocisplatin On Mtp Polysupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro

Parker

Petluru

et al. 2010

Molecular Cancer Therapeutics

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“…In addition, it is also able to produce microtubule disassembly by direct tubulin modification (e.g., when platinated, tubulin does not assemble into microtubules, consequently altering MT dynamics) (Boekelheide et al 1992;Tulub and Stefanov 2001). In our studies, we did not observe tau hyperphosphorylation at the low/high doses used in the study for the treatments with cisplatin.…”

Section: Discussionmentioning

confidence: 46%

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

2008

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Neurofibrillary tangles are one of the pathologic hallmarks of Alzheimer's disease (AD). They are composed of paired helical filaments (PHF) containing hyperphosphorylated forms of tau. Hyperphosphorylation of certain tau sites favors its dissociation from the microtubules (MT), interfering with axonal transport and compromising the function and viability of neurons. Reappearance of cell cycle proteins have been reported in neurons exhibiting tau aggregation, suggesting that an aberrant cell cycle occurs before neurons die. Cell cycle suppression in neurons is crucial to survival, thus prevention of progression through the cell cycle may offer a therapeutic approach. Using a neuroblastoma cell line overexpressing 3-repeat (3R) tau, we investigated the effects of cell cycle inhibitors on tau phosphorylation. G2/M phase inhibitors did not alter phosphorylation of tau at Ser-202 and Ser-396/404 at the lower doses, but did at higher doses. Ser-202 and Ser-396/404 are phosphorylation sites of early and late neurofibrillary tangles, respectively, in AD. Cisplatin, a G1 phase inhibitor, did not phosphorylate tau. Cyclophosphamide and phosphoramide mustard, DNA cross-linking agents, decreased tau phosphorylation at Ser-396/404 site, but increased phosphorylation at Ser-202. These studies demonstrate that the G2/M blockers have a dose-dependent effect on tau phosphorylation. This seems to be a consequence of both the disruption of MT-organization and MT-dynamics when doses are higher, but only a disruption of MT-dynamics with lower doses. These results are also in agreement with the lack of phosphorylation seen for cisplatin, another inhibitor that produces disruption of the MT-dynamics.

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Mechanisms of resistance of human small cell lung cancer lines selected in VP-16 and cisplatin

Jain

Lam

Pym

et al. 1996

Cancer

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cis-Diamminedichloroplatinum (II) (cisplatin) alters microtubule assembly dynamics

Cited by 34 publications

References 41 publications

BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro

BNP7787-Mediated Modulation of Paclitaxel- and Cisplatin-Induced Aberrant Microtubule Protein Polymerization In vitro

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

Mechanisms of resistance of human small cell lung cancer lines selected in VP-16 and cisplatin

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