The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review

Wang, Long G.; Liu, Xiao M.; Kreis, Willi; Budman, Daniel R.

doi:10.1007/s002800050989

Cited by 351 publications

(259 citation statements)

References 64 publications

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“…We show that GIST-S cells are resistant to docetaxel alone but in combination with MP470 are sensitive to synergistic cell killing. Docetaxel inhibits tumor growth by induction of microtubule stabilization, promotion of BCL-2 phosphorylation and inactivation leading to p53-and p21-driven apoptosis (Haldar et al, 1997;Wang et al, 1999). As GIST patients overexpress BCL-2 (80%), the strategy of targeting KIT/AXL and BCL-2 together appears feasible.…”

Section: Discussionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

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Section: Discussionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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“…Induction of p53 and p21 by antimicrotubule agents has been considered to be one mechanism involved in the apoptotic process in cancer cells (Blagosklonny et al, 1995;Barboule et al, 1997;Torres and Horwitz, 1998;Wang et al, 1999b). To explore whether vinorelbine and paclitaxel are able to induce p21 expression in AD and AI cells that are deficient in p21, and the possible differences between AD and AI cells in expression of p53 and p21 in response to treatments with vinorelbine or paclitaxel, the resultant levels of p53 and p21 were determined by Western blotting.…”

Section: Induction Of P53 and P21 Wafi/c1p1 Expression By Vinorelbinementioning

confidence: 99%

“…In contrast to paclitaxel, vinorelbine binds microtubules and prevents their polymerisation, thus interfering with mitosis (Krikorian and Breillout, 1991). Previous studies have demonstrated that independent of the type of effect by the antimicrotubule agent on microtubule assembly (polymerisation or depolymerisation), these drugs exhibit the ability to promote apoptosis in cancer cells (Wang et al, 1999bBudman et al, 2000;Charles et al, 2001;Fan et al, 2001;Liu et al, 2001). One of mechanisms of vinorelbine-induced apoptosis is thought to be the upregulation of p21 and p53.…”

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Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

et al. 2003

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To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent (AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21 WAFl/CIP1 (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine (Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Spl-3 and Spl-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer.

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“…Specifically, c-Src has been found to be highly activated in colon cancer metastasized to the liver (Mao et al, 1997) and mutation in the regulatory domain of c-Src has been reported as a mechanism of Src activation in human colon cancer (Irby et al, 1999). Although a number of signal transduction pathways toward Bcl-2 phosphorylation have been reported as an apoptotic mechanism induced by taxanes (Wang et al, 1999), the role of Src in these processes has yet to be determined. Src transduces a variety of signals to downstream signal transduction cascades including Ras (Brown and Cooper, 1996).…”

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confidence: 99%

Src tyrosine kinase augments taxotere-induced apoptosis through enhanced expression and phosphorylation of Bcl-2

Boudný

Nakano

2002

Br J Cancer

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Activation of Src, which has an intrinsic protein tyrosine kinase activity, has been demonstrated in many human tumours, such as colorectal and breast cancers, and is closely associated with the pathogenesis and metastatic potential of these cancers. In this study, we have examined the effect of activated Src on the sensitivity to taxotere, an anticancer drug targeting microtubules, using v-src-transfected HAG-1 human gall bladder epithelial cells. As compared with parental HAG-1 cell line, vsrc-transfected HAG/src3-1 cells became 5.9 and 7.0-fold sensitive to taxotere for 2 and 24-h exposure, respectively. By contrast, HAG-1 cells transfected with activated Ras, which acts downstream of Src, acquired approximately 2.5*4.8-fold taxotere resistance. The taxotere sensitivity in HAG/src3-1 cells was reversed, if not completely, by herbimycin A, a specific inhibitor of Src family protein tyrosine kinase, indicating that Src protein tyrosine kinase augments sensitivity to taxotere. Treatment of HAG/src3-1 cells with taxotere resulted in phosphorylation of Bcl-2 and subsequent induction of apoptotic cell death, whereas neither Bcl-2 phosphorylation nor apoptosis occurred in parental or c-H-ras-transfected HAG-1 cells. Interestingly, the Bcl-2 protein is overexpressed in v-src-transfected cell line, compared to those in parental or Ras-transfected cell line. Treatment of HAG/src3-1 cells with herbimycin A significantly reduced the expression and phosphorylation of Bcl-2, and abrogated taxotere-induced apoptosis, suggesting a potential role for Src protein tyrosine kinase in the taxotere-induced apoptotic events. H-7, a protein kinase C inhibitor and wortmannin, a phosphatidylinositol-3 kinase (PI-3 kinase) inhibitor, neither altered taxotere sensitivity nor inhibited taxotere-induced apoptosis in these cells. These data indicate that the ability of activated Src to increase taxotere sensitivity would be mediated by apoptotic events occurring through Src to downstream signal transduction pathways toward Bcl-2 phosphorylation, but not by activated Ras, PI-3 kinase or protein kinase C.

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The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review

Cited by 351 publications

References 64 publications

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Src tyrosine kinase augments taxotere-induced apoptosis through enhanced expression and phosphorylation of Bcl-2

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