Characterization of the Taxol Binding Site on the Microtubule

Rao, Srinivasa P. S.; He, Liangmei; Chakravarty, Sudip; Ojima, Iwao; Orr, George A.; Horwitz, Susan Band

doi:10.1074/jbc.274.53.37990

Cited by 169 publications

(110 citation statements)

References 30 publications

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“…This difference could be due to the differences in platinum and taxane mechanisms of action. Platinums act mainly by forming nuclear platinum adducts on DNA strands (Fuertes et al 2003;Go et al 1999), while taxanes act by stabilising microtubules within the cell (Manfredi et al 1984;Rao et al 1995). Another caveat is that the cell lines used in this study were of different genetic backgrounds having been obtained from different patients.…”

Section: Resistance Developmentmentioning

confidence: 99%

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

Busschots

O’Toole

O’Leary

et al. 2015

Experimental Cell Research

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Section: Resistance Developmentmentioning

confidence: 99%

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

Busschots

O’Toole

O’Leary

et al. 2015

Experimental Cell Research

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“…Pharmacological stabilization of microtubules by paclitaxel affects tau binding (15,16). We hypothesized that the opposite may also occur; physiological stabilization of microtubules by tau may reduce paclitaxel binding to tubulin.…”

Section: Microtubules Formed In the Presence Of Tau Bind Less Paclitamentioning

confidence: 99%

Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer

Rouzier

Rajan

Wagner

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

380

301

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Breast cancers show variable sensitivity to paclitaxel. There is no diagnostic test to identify tumors that are sensitive to this drug. We used U133A chips to identify genes that are associated with pathologic complete response (pCR) to preoperative paclitaxelcontaining chemotherapy in stage I-III breast cancer (n ‫؍‬ 82). Tau was the most differentially expressed gene. Tumors with pCR had significantly lower (P < 0.3 ؋ 10 ؊5 ) mRNA expression. Tissue arrays from 122 independent but similarly treated patients were used for validation by immunohistochemistry. Seventy-four percent of pCR cases were tau protein negative; the odds ratio for pCR was 3.7 (95% confidence interval, 1.6 -8.6; P ϭ 0.0013). In multivariate analysis, nuclear grade (P < 0.01), age <50 (P ϭ 0.03), and taunegative status (P ϭ 0.04) were independent predictors of pCR. Small interfering RNA experiments were performed to examine whether down-regulation of tau increases sensitivity to chemotherapy in vitro. Down-regulation of tau increased sensitivity of breast cancer cells to paclitaxel but not to epirubicin. Tubulin polymerization assay was used to assess whether tau modulates binding of paclitaxel to tubulin. Preincubation of tubulin with tau resulted in decreased paclitaxel binding and reduced paclitaxelinduced microtubule polymerization. These data suggest that low tau expression renders microtubules more vulnerable to paclitaxel and makes breast cancer cells hypersensitive to this drug. Low tau expression may be used as a marker to select patients for paclitaxel therapy. Inhibition of tau function might be exploited as a therapeutic strategy to increase sensitivity to paclitaxel. adjuvant therapy ͉ drug resistance

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“…8 In fact, molecular alterations in the 2 paclitaxel binding regions: amino acids 1-31 and amino acids 217-231, have been reported as a possible cause of specific drug resistance. 9 Based on the hypothesis of a possible clinical relevance for altered b-tubulin characteristics and considering that only b-tubulin mutations have been episodically analyzed in human breast cancer, 10,11 we studied b-tubulin mutations and its isotypes' expression in a panel of breast cancer cell lines differing in paclitaxel sensitivity. Successively, we verified the clinical validity of the in vitro results in a series of breast cancer patients treated with taxol based chemotherapy.…”

mentioning

confidence: 99%

Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of β‐tubulins

Tommasi¹,

Mangia²,

Lacalamita³

et al. 2007

Intl Journal of Cancer

139

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The antineoplastic effect of paclitaxel is mainly related to its ability to bind the b subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. The relevance of the Class I b-tubulin characteristics have also been confirmed in the clinical setting where mutations of paclitaxel-binding site of b-tubulin Class I have been related to paclitaxel resistance in non small cell lung and ovarian cancers. In the present study, we verified the hypothesis of a relationship between molecular alterations of b-tubulin Class I and paclitaxel sensitivity in a panel of breast cell lines with different drug IC 50 . The Class I b-tubulin gene cDNA has been sequenced detecting heterozygous missense mutations (exon 1 and 4) only in MCF-7 and SK-BR-3 lines. Furthermore, the expression (at both mRNA and protein level) of the different isotypes have been analyzed demonstrating an association between low cell sensitivity to paclitaxel and Class III b-tubulin expression increasing. Antisense oligonucleotide (ODN) experiments confirmed that the inhibition of Class III b-tubulin could at least partially increase paclitaxel-chemosensitivity. The hypothesis of a relationship between b-tubulin tumor expression and paclitaxel clinical response has been finally verified in a series of 92 advanced breast cancer patients treated with a first line paclitaxel-based chemotherapy. Thirty-five percent (95% CI: 45-31) of patients with high Class III b-tubulin expression showed a disease progression vs. only 7% of patients with low expression (35% vs. 7%, p < 0.002). Our study suggests that Class III b-tubulin tumor expression could be considered a predictive biomarker of paclitaxel-clinical resistance for breast cancer patients. ' 2007 Wiley-Liss, Inc.

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Characterization of the Taxol Binding Site on the Microtubule

Cited by 169 publications

References 30 publications

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer

Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of β‐tubulins

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