Synergistic Suppression of Microtubule Dynamics by Discodermolide and Paclitaxel in Non-Small Cell Lung Carcinoma Cells

Honoré, Stéphane; Kamath, Kathy; Braguer, Diane; Horwitz, Susan Band; Wilson, Leslie; Briand, Claudette; Jordan, Mary Ann

doi:10.1158/0008-5472.can-04-0693

Cited by 100 publications

(117 citation statements)

References 36 publications

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“…In previous studies, dynamicity was reduced by 25-64% in conjunction with drug-induced inhibition of cell proliferation or mitotic arrest in A498, CaOV3, A549, and MCF7 cancer cell lines (6,12,13). Consistent with these results, in ␤I-overexpressing CHO cells, dynamicity was reduced by 47%.…”

Section: Overexpression Of ␤Iii-tubulin Does Not Cause An Inherent Insupporting

confidence: 80%

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βIII-Tubulin Induces Paclitaxel Resistance in Association with Reduced Effects on Microtubule Dynamic Instability

Kamath

Wilson

Cabral

et al. 2005

Journal of Biological Chemistry

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236

175

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The development of resistance to paclitaxel in tumors is one of the most significant obstacles to successful therapy. Overexpression of the ␤III-tubulin isotype has been associated with paclitaxel resistance in a number of cancer cell lines and in tumors, but the mechanism of resistance has remained unclear. Paclitaxel inhibits cancer cell proliferation by binding to the ␤-subunit of tubulin in microtubules and suppressing microtubule dynamic instability, leading to mitotic arrest and cell death. We hypothesized that ␤III-tubulin overexpression induces resistance to paclitaxel either by constitutively enhancing microtubule dynamic instability in resistant cells or by rendering the microtubules less sensitive to the suppression of dynamics by paclitaxel. Using Chinese hamster ovary cells that inducibly overexpress either ␤I-or ␤III-tubulin, we analyzed microtubule dynamic instability during interphase by microinjection of rhodamine-labeled tubulin and time-lapse fluorescence microscopy. In the absence of paclitaxel, there were no differences in any aspect of dynamic instability between the two ␤-tubulin-overexpressing cell types. However, in the presence of 150 nM paclitaxel, dynamic instability was suppressed to a significantly lesser extent (suppressed only 12%) in cells overexpressing ␤III-tubulin than in cells overexpressing similar levels of ␤I-tubulin (suppressed 47%). The results suggest that overexpression of ␤III-tubulin induces paclitaxel resistance by reducing the ability of paclitaxel to suppress microtubule dynamics. The results also suggest that endogenous regulators of microtubule dynamics may differentially interact with individual tubulin isotypes, supporting the idea that differential expression of tubulin isotypes has functional consequences in cells.

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Section: Overexpression Of ␤Iii-tubulin Does Not Cause An Inherent Insupporting

confidence: 80%

“…Because the lowest concentrations of paclitaxel that effectively inhibit cell proliferation and block mitosis suppress microtubule dynamics (6,12,13) without significantly increasing microtubule polymer levels, suppression of microtubule dynamics appears to be its most potent mechanism of mitotic arrest (14).…”

mentioning

confidence: 99%

βIII-Tubulin Induces Paclitaxel Resistance in Association with Reduced Effects on Microtubule Dynamic Instability

Kamath

Wilson

Cabral

et al. 2005

Journal of Biological Chemistry

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236

175

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“…Synergistic interactions of anticancer drugs have been reported in studies of tumor cell lines (2 -4), animal models (5), and cancer patients (6). Such interactions include, but are not limited to, the combination of discodermolide and paclitaxel (2), capsicum and green tea concentrate (4), gemcitabine and docetaxel (6), docosahexaenoic acid (DHA) and paclitaxel (7,8), and irinotecan and 5-fluorouracil (5).…”

Section: Introductionmentioning

confidence: 99%

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

Ding

Liu

Vaught

et al. 2006

Molecular Cancer Therapeutics

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Clioquinol, an 8-hydroxyquinoline derivative (5-chloro-7-iodo-8-hydroxyquinoline) with antimicrobial properties, has recently been found to have cytotoxic activity towards human cancer cell lines at concentrations achieved by oral administration. This study was initiated to determine whether clioquinol could potentiate the antitumor effects of two drugs, doxorubicin and docosahexaenoic acid (DHA), believed to act in part via the generation of reactant oxidant species. At low micromolar concentrations, clioquinol had little effect upon cell viability and did not potentiate doxorubicin's cytotoxicity. Clioquinol significantly enhanced DHA's cytotoxic effects, an interaction that was shown to be synergistic by isobolographic analysis. Clioquinol exhibited a synergistic interaction with DHA in reducing nuclear factor-KB activity and inducing apoptosis, and the combination reduced the level of several molecules that promote cell survival, including Akt, p65, and Bcl-2. Interestingly, clioquinol neither induced lipid peroxidation itself nor increased peroxidation brought about by the addition of DHA. However, when cells were pretreated with antioxidant vitamin E, the synergism of clioquinol and DHA was blocked, indicating the essential role of lipid peroxidation for their action. These findings reveal a novel antitumor drug combination that synergistically targets major cell survival signaling pathways.

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“…The binding of bryostatin I to its receptors down-regulates protein kinase C isoforms in various tumor cells, leading to inhibition of growth, alteration of differentiation and/or cell death [164]. This compound was granted orphan drug status by the [165], is a microtubule-stabilizing drug [166][167]. Halichondrin E7389 82, a derivative of halichondrin B isolated from Halichondria okadai, was found to inhibit tumor cell proliferation in association with the G 2 /M arrest and microtubule polymerization [168].…”

Section: Krx-0601mentioning

confidence: 99%

Natural products as lead compounds in drug discovery

Khazir

Mir

et al. 2013

Journal of Asian Natural Products Research

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Abstract:This review surveys the diversity of natural products derived from terrestrial plants, microorganisms, marine organisms and fungi and utilised in the treatment of various diseases.A wide spectrum of compounds derived from these sources has found many applications in the fields of medicine, pharmacy and general biology. The enormous structural diversity of natural products and their medicinal significance has led researchers to predict that screening natural resources will generate new -lead‖ compounds. It is well established that structural analogues with greater pharmacological activity and fewer side effects can be generated by molecular modification of the functional groups of such lead compounds.

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Synergistic Suppression of Microtubule Dynamics by Discodermolide and Paclitaxel in Non-Small Cell Lung Carcinoma Cells

Abstract: ABSTRACT

Cited by 100 publications

References 36 publications

βIII-Tubulin Induces Paclitaxel Resistance in Association with Reduced Effects on Microtubule Dynamic Instability

βIII-Tubulin Induces Paclitaxel Resistance in Association with Reduced Effects on Microtubule Dynamic Instability

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells

Natural products as lead compounds in drug discovery

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