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PubMed1976

Structure and control of assembly of cytoplasmic microtubules in normal and transformed cells.

Indirect immunofluorescence analyses using antibodies directed against 6S tubulin have shown an elaborate cytoplasmic microtubule complex (CMTC) in nontransformed cells in culture. The CMTC is strikingly altered in cells that have been transformed spontaneously by viruses or by chemicals. Assembly of microtubules in vitro and in vivo is markedly inhibited in the presence of elevated levels of calcium. Alteration of the surface of normal cells by brief treatment with low concentrations of trypsin initiate a rapid breakdown of cytoplasmic microtubules. Finally, a hypothesis is presented relating microtubule assembly and surface membrane modulation suggesting that calcium is the primary modulating signal.

Antibodies↗
PubMed1991

Inhibition of microtubule assembly is a possible mechanism of action of mitoxantrone.

We have found that mitoxantrone can inhibit the polymerization of brain tubulin in a dose dependent manner. MXT had relatively high affinity for tubulin but had no appreciable effect on tubulin associated guanosine-triphosphatase (GTPase) activity nor could it compete with vinblastine (VB) and colchicine (Col) for tubulin binding sites. Furthermore, MXT (0.1-10 microM) is antiproliferative to cold-treated (0 degree C) epithelial cells after only brief exposure (30 min). These results indicated that MXT is a microtubule inhibitory agent and can exert its anticellular effect through modulation of microtubule assembly.

Animals↗
PubMed2004

A comparative analysis of alphaA- and alphaB-crystallin expression during the cell cycle in primary mouse lens epithelial cultures.

AlphaA- and alphaB-crystallins are small heat shock proteins and molecular chaperones that prevent non-specific aggregation of denaturing proteins. Previous work in our laboratory has shown that lens epithelial cells derived from alphaA-/- mice exhibit slower growth, whereas alphaB-/- lens epithelial cells hyperproliferate at a higher rate in culture [Andley et al., J. Biol. Chem. 273 (1998) 31252; FASEB J. 15 (2001) 221]. Although both have been implicated in apoptosis and cell proliferation, direct analysis of their expression during the cell cycle has not been investigated. This study was undertaken to define the expression levels of alphaA and alphaB-crystallins during the cell cycle. Primary lens epithelial cell cultures derived from wild type mice were synchronized by serum starvation, and pulsed with bromodeoxyuridine (BrdU) at different times after re-stimulation with serum. Dual parameter flow cytometric studies with BrdU and propidium iodide (PI)-labeled cells were performed. Cells entered S phase 14 hr after serum re-stimulation. The duration of the S phase was 6 hr, and the total cell cycle transit time was between 24-27 hr. Enhanced expression of cyclin A, a protein essential for DNA synthesis was used as an additional marker to define the initiation of the S phase. Immunoblotting analysis demonstrated that the expression of alphaA and alphaB-crystallin was up to 10-fold higher in cells synchronized in G0 phase than in G1 phase. The levels of the proteins increased three-fold again as the cells entered the S phase and progressed to mitosis, but did not rise to the levels observed in G0 phase. This increase in expression of alphaA-crystallin resulted in part from enhanced synthesis during the S phase, as shown by an increase in [35S]methionine-labeling and immunoprecipitation of the radiolabeled alphaA-crystallin. The results were further confirmed by flow cytometric analysis using DNA content and alphaA-crystallin expression. The increase in alphaB-crystallin in S phase was paralleled by an increase in gene expression as shown by real-time RT-PCR analysis. These results demonstrate for the first time that in lens epithelial cells, alphaA and alphaB-crystallin levels are modulated during the cell cycle. Since the absence of alphaA and alphaB- crystallin in lens epithelial cells has been associated with disturbance of the tubulin cytoskeleton during mitosis, and with increased cell death or genomic instability, our results indicating that the alphaA- and alphaB-crystallin expression increases prior to mitosis are significant. The differential expression of these crystallins in the cell cycle may be important for optimal lens epithelial growth and lens transparency.

Animals↗
PubMed2002

Shigella deliver an effector protein to trigger host microtubule destabilization, which promotes Rac1 activity and efficient bacterial internalization.

Shigella deliver a subset of effectors into the host cell via the type III secretion system, that stimulate host cell signal pathways to modulate the actin dynamics required for invasion of epithelial cells. Here we show that one of the Shigella effectors, called VirA, can interact with tubulin to promote microtubule (MT) destabilization, and elicit protrusions of membrane ruffling. Under in vitro conditions, VirA inhibited polymerization of tubulin and stimulated MT destabilization. Upon microinjection of VirA into HeLa cells, a localized membrane ruffling was induced rapidly. Overexpression of VirA in host cells caused MT destruction and protruding membrane ruffles which were absent when VirA was co-expressed with a dominant-negative Rac1 mutant. Indeed, Shigella but not the virA mutant stimulated Rac1, including the formation of membrane ruffles in infected cells. Importantly, the MT structure beneath the protruding ruffling was destroyed. Furthermore, drug-induced MT growth in HeLa cells greatly enhanced the Shigella entry. These results indicate that VirA is a novel type of bacterial effector capable of inducing membrane ruffling through the stimulation of MT destabilization.

Actins↗
PubMed1997

Regulation of microtubule dynamics by Ca2+/calmodulin-dependent kinase IV/Gr-dependent phosphorylation of oncoprotein 18.

Oncoprotein 18 (Op18; also termed p19, 19K, p18, prosolin, and stathmin) is a regulator of microtubule (MT) dynamics and is phosphorylated by multiple kinase systems on four Ser residues. In addition to cell cycle-regulated phosphorylation, external signals induce phosphorylation of Op18 on Ser-25 by the mitogen-activated protein kinase and on Ser-16 by the Ca2+/calmodulin-dependent kinase IV/Gr (CaMK IV/Gr). Here we show that induced expression of a constitutively active mutant of CaMK IV/Gr results in phosphorylation of Op18 on Ser-16. In parallel, we also observed partial degradation of Op18 and a rapid increase of total cellular MTs. These results suggest a link between CaMK IV/Gr, Op18, and MT dynamics. To explore such a putative link, we optimized a genetic system that allowed conditional coexpression of a series of CaMK IV/Gr and Op18 derivatives. The result shows that CaMK IV/Gr can suppress the MT-regulating activity of Op18 by phosphorylation on Ser-16. In line with these results, by employing a chemical cross-linking protocol, it was shown that phosphorylation of Ser-16 is involved in weakening of the interactions between Op18 and tubulin. Taken together, these data suggest that the mechanism of CaMK IV/Gr-mediated suppression of Op18 activity involves both partial degradation of Op18 and direct modulation of the MT-destabilizing activity of this protein. These results show that Op18 phosphorylation by CaMK IV/Gr may couple alterations of MT dynamics in response to external signals that involve Ca2+.

Calcium-Calmodulin-Dependent Protein Kinase Type 4↗
PubMed1997

PDGF-BB increases endothelial migration on cord movements during angiogenesis in vitro.

To explore direct effects of platelet-derived growth factor (PDGF) on endothelial cells during angiogenesis in vitro, we have used cloned bovine aortic endothelial cells that spontaneously form cord structures. Recently we have shown that cells forming these endothelial cords express PDGF beta-receptors and that PDGF-BB can contribute to cellular proliferation and cord formation. In this study we investigated whether PDGF-induced cellular migration might also contribute to endothelial repair and angiogenesis in vitro. Ten individual endothelial cells in cords were tracked at an early stage of cord formation by video-timelapse microscopy. PDGF-BB (100 ng/ml) induced an increase in endothelial cell movement of 67 +/- 15% as compared with diluent control. Interestingly, PDGF-BB also increased movements of entire cord structures, followed at branching points, by 53 +/- 12% over diluent control. Taken together, these video-timelapse experiments suggested that the apparent movements of single endothelial cord cells might also be due to the motion of entire underlying cord structures in response to PDGF. To analyze the response of single endothelial cord cells we therefore examined whether PDGF-induced migration contributes to endothelial repair. Abrasions were applied with a razor blade to confluent monolayers of endothelial cells at an intermediate stage of cord formation. PDGF-BB concentration-dependently increased the distance to which cord-forming endothelial cells migrated into the abrasion. An increased number of elongated, i.e., probably migrating, endothelial cells was found in the abrasion in response to PDGF-BB. However, there was no effect of PDGF-BB on the total number of endothelial cells found in the abrasion. PDGF-AA affected neither the distance to which the cells migrated nor the number of elongated cells. Actin and tubulin stainings revealed that these cytoskeletal structures were not appreciably altered by PDGF-BB. Furthermore, urokinase-type plasminogen activator transcripts were not modulated in response to PDGF-BB. We conclude that in this model of angiogenesis in vitro PDGF-BB can elicit the movement of entire cord structures, possibly via u-PA-independent mechanisms. PDGF-BB also controls the migration of single cord-forming endothelial cells. Thus, PDGF-BB possibly contributes to endothelial repair and angiogenesis by direct effects on proliferation and composite movements of PDGF beta-receptor-expressing endothelial cells and cords.

Adult↗
PubMed1994

Effects of calcium-binding proteins on histamine release from permeabilized rat peritoneal mast cells.

Among the calcium-binding proteins from chicken gizzard smooth muscle, smooth muscle calcium-binding protein 11 (SMCaBP 11), which is an EF-hand type calcium-binding protein, can prevent Ca2+ dependent histamine release from permeabilized rat peritoneal mast cells. This activity appears to be specific since other calcium-binding proteins (CaBPs), including h-calcimedin, l-calcimedin, calmodulin and S100, had no inhibitory action. Approximately 40% of the histamine release was inhibited by SMCaBP 11 at 48 nM and the half-maximal inhibition occurred at 20 nM. Immunological techniques revealed that permeabilized mast cells elicited by Ca2+ also released actin into the medium, but not tubulin. The addition of SMCaBP 11 prevented the secretion of actin from the mast cells, though the distribution of F-actin was only slightly affected. These findings suggest that SMCaBP 11 may modulate Ca2+ and actin-mediated exocytosis from permeabilized mast cells.

Actins↗
PubMed2004

Molecular bases for sensitivity to tubulin-binding herbicides in green foxtail.

We investigated the molecular bases for resistance to several classes of herbicides that bind tubulins in green foxtail (Setaria viridis L. Beauv.). We identified two alpha- and two beta-tubulin genes in green foxtail. Sequence comparison between resistant and sensitive plants revealed two mutations, a leucine-to-phenylalanine change at position 136 and a threonine-to-isoleucine change at position 239, in the gene encoding alpha2-tubulin. Association of mutation at position 239 with herbicide resistance was demonstrated using near-isogenic lines derived from interspecific pairings between green foxtail and foxtail millet (Setaria italica L. Beauv.), and herbicide sensitivity bioassays combined with allele-specific PCR-mediated genotyping. Association of mutation at position 136 with herbicide resistance was demonstrated using herbicide sensitivity bioassays combined with allele-specific PCR-mediated genotyping. Both mutations were associated with recessive cross resistance to dinitroanilines and benzoic acids, no change in sensitivity to benzamides, and hypersensitivity to carbamates. Using three-dimensional modeling, we found that the two mutations are adjacent and located into a region involved in tubulin dimer-dimer contact. Comparison of three-dimensional alpha-tubulin models for organisms with contrasted sensitivity to tubulin-binding herbicides enabled us to propose that residue 253 and the vicinity of the side chain of residue 251 are critical determinants for the differences in herbicide sensitivity observed between organisms, and that positions 16, 24, 136, 239, 252, and 268 are involved in modulating sensitivity to these herbicides.

Amino Acid Sequence↗
PubMed2004

Resistance to microtubule-targeted cytotoxins in a K562 leukemia cell variant associated with altered tubulin expression and polymerization.

A vinblastine resistant cell line, KCVB2, was established by co-selecting the parental erythroleukemic cell line K562 with step-wise increased concentrations of vinblastine (Velban) in the presence of the cyclosporin D analogue PSC 833 (2 microM), a potent modulator of the multidrug resistance phenotype. KCVB2 cells are 8-fold resistant to the selecting agent, vinblastine, but also exhibit significant resistance to other vinca alkaloids, including 14-fold resistance to vinorelbine, as well as 6-fold cross-resistance to paclitaxel. Doubling time and morphology were similar to the parental K562 cells. Rt-PCR analysis revealed no alterations in the expression of the mdr1 and MRP genes. Intracellular vinblastine accumulation was unchanged. Disruption of the mitotic spindles and multiple mitotic asters occurred in both cell lines but required higher concentrations of vinblastine in KCVB2 cells than in K562 cells. Significant differences were observed in the tubulin content of KCVB2 cells: reduction of total tubulin content, increased polymerized fraction of total tubulin, and overexpression of class III beta-tubulin which is expressed at very low levels in the parental K562 cells. K562 cells transfected with murine class III beta-tubulin did not display the resistance pattern observed in KCVB2 cells. Revertants of KCVB2 manifested reversion to parental drug sensitivity, an increase in total tubulin level, and a decrease in polymerized tubulin. In conclusion, the KCVB2 cell line displays a novel mechanism of resistance to both depolymerizing and stabilizing microtubule-targeted cytotoxins which does not involve altered cellular drug accumulation, but corresponds to alterations in the total tubulin content and polymerization status, and may involve an effect on microtubule dynamics.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Entropy and information in flagellar axoneme cybernetics: a radial spokes integrative function.

Radial spokes and the consequences of their relationships with the central apparatus seem to play a very important role in the regulation of axonemal activity. We modeled their behavior and observed that it appears to differ in the cilium and the flagellum with respect to the development of bending as a function of time. Specifically, our calculation raises the question of the real function of the radial spokes in the regulation of the axoneme, because a given curvature of the flagellar axoneme may correspond to two opposite of their tilts. The stable nil/low amplitude shear points that we had characterized along the flagellum allowed us to describe their axoneme as a series of modules [Cibert, 2002: Cell Motil. Cytoskeleton 51:89-111]. We observed that a nil/low shearing point moves along each module during beating when a new bend is created at the base of the flagellum [Cibert, 2001: Cell Motil. Cytoskeleton 49:161-175]. We propose that the structural gradients of isoforms of tubulin could be basic verniers that act as structural references for the axonemal machinery during the beating. This allowed us to interpret the axonemal organization as a segmented structure, that could be analyzed according to the complexion(1) theory and Shannon's information theory, which associate entropy and probability in the creation of information. The important consequence of this interpretation is that regulation of the axonemal machinery appears to be due to the upstream and downstream cross-talk between the axonemal segments that do not involve any dedicated integrative structure but depend on the energy level of the entire length of each module.

Biomechanical Phenomena↗
PubMed1999

Pyruvate kinase as a microtubule destabilizing factor in vitro.

Endogenous control of microtubule dynamism is essential in many cell types. Numerous microtubule-adhering proteins stabilize the polymer status, while very few protein factors are described with opposite effects. The brain- and muscle-specific M1 isoform of the enzyme pyruvate kinase is investigated here in this respect. Three pieces of evidence indicate antimicrotubular effects of this protein. (1) Pyruvate kinase inhibits taxol-induced tubulin polymerization into microtubules as revealed by turbidimetry. (2) Pelleting experiments show that pyruvate kinase partially disassembles taxol-stabilized microtubules into less sedimentable oligomers leading to the appearance of tubulin in the supernatant fractions. (3) Electron microscopy reveals the kinase-induced formation of great amounts of thread-like tubulin oligomers which tend to accumulate in a light/less sedimentable fraction. Immunoelectron micrographs using labeled antibody against pyruvate kinase provide evidence for the binding of pyruvate kinase to the thread-like oligomeric forms. The present data allow the assumption that pyruvate kinase may display multiple regulatory functions as a glycolytic control enzyme and as a modulator of microtubule dynamism.

Animals↗
PubMed2003

Protein tyrosine nitration is triggered by nerve growth factor during neuronal differentiation of PC12 cells.

Nitric oxide (NO) is a signaling molecule implicated in a spectrum of cellular processes including neuronal differentiation. The signaling pathway triggered by NO in physiological processes involves the activation of soluble guanylate cyclase and S-nitrosylation of proteins, and, as recently proposed, nitration of tyrosine residues in proteins. However, little is known about the mechanisms involved and the target proteins for endogenous NO during the progression of neuronal differentiation. To address this question, we investigated the presence, localization, and subcellular distribution of nitrated proteins during neurotrophin-induced differentiation of PC12 cells. We find that some proteins show basal levels of tyrosine nitration in PC12 cells grown in the absence of nerve growth factor (NGF) and that nitration levels increase significantly after 2 days of incubation with this neurotrophin. Nitrated proteins accumulate over a period of several days in the presence of NGF. We demonstrate that this nitration is coupled to activation of nitric oxide synthase. The subcellular distribution of nitrated proteins changes during PC12 cell differentiation, displaying a shift from the cytosolic to the cytoskeletal fraction and we identified alpha-tubulin as the major target of nitration in PC12 cells by N-terminal sequence and MALDI-TOF analyses. We conclude that tyrosine nitration of proteins could be a novel molecular mechanism involved in the signaling pathway by which NO modulates NGF-induced differentiation in PC12 cells.

Animals↗
PubMed1997

Inhibition of tumor invasiveness by 1alpha,25-dihydroxyvitamin D3 coupled to a decline in protein kinase A activity and an increase in cytoskeletal organization.

The capacity of cloned metastatic Lewis lung carcinoma cells (LLC-LN7) to invade through reconstituted basement membrane-coated filters was reduced after incubation with 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. This was observed at doses as low as 10(-10) M 1,25(OH)2D3. The 1,25(OH)2D3-treated cells also had reduced levels of protein kinase A (PKA) activity and an increase in the level of polymerized actin, properties that have previously been demonstrated for less metastatic LLC variants. In addition, levels of the intermediate filament protein vimentin increased in 1,25(OH)2D3-treated LLC-LN7 tumor cells. In contrast, the levels and distribution of tubulin were not affected by 1,25(OH)2D3. The possibility that the decline in PKA activity was involved in the 1,25(OH)2D3 modulation of the cytoskeletal components was evaluated. To accomplish this, LLC-7 transfectants whose PKA levels were blocked due to expression of a mutated PKA R(1alpha) subunit (LN7-REV) were incubated with 1,25(OH)2D3 and their levels of F-actin were measured. In the absence of 1,25(OH)2D3 treatment, the PKA-defective LN7-REV cells had an increased level of polymerized actin as compared to the wild-type LLC-LN7 cells. This level of F-actin was minimally affected by 1,25(OH)2D3, suggesting that PKA activity is required for 1,25(OH)2D3 modulation of actin polymerization. These studies show that 1,25(OH)2D3 can reduce PKA activity in tumor cells, and that this reduction in PKA may be an intermediate signal through which 1,25(OH)2D3 affects the cytoskeleton and diminishes tumor invasiveness.

Animals↗
PubMed2005

Role of Ser50 phosphorylation in SCG10 regulation of microtubule depolymerization.

Members of the stathmin-like protein family depolymerize microtubules (MTs), probably due to the ability of each stathmin monomer to bind two tubulin heterodimers in a complex (T(2)S complex). SCG10, a member of this family, is localized in the growth cone of neurons. It has four identified sites of serine phosphorylation (S50, S63, S73, and S97). Of these, S50 and S97 are phosphorylated by cAMP-dependent protein kinase, an enzyme involved in growth cone guidance. When the equivalent sites in stathmins are phosphorylated, they lose their ability to depolymerize MTs. We investigated the specific role of the two cAMP-dependent protein kinase (PKA) phosphorylation sites in SCG10. A mutant of SCG10 phosphorylated only on S50 retained the ability to depolymerize MTs, but SCG10 phosphorylated on S97 or on both S50 and S97 lost MT-depolymerizing activity. Surface plasmon resonance studies revealed that the phosphorylation of SCG10 at these sites reduced the tubulin heterodimer binding, mainly due to a reduced rate of association. In particular, compared to the two other phosphorylated forms, SCG10 phosphorylated at S50 had a significantly smaller dissociation constant for the binding of the first tubulin heterodimer and larger association and dissociation rate constants for the binding of the second heterodimer. This indicates that the phosphorylation of S50 compensates for the effect of phosphorylation at other sites by modulating T2S complex formation. Furthermore, these results suggest that S50-P maintains MT-depolymerizing activity, which indicates that the biological functions of phosphorylation at S50 and S97 are different.

Animals↗
PubMed2002

beta-Tubulin C354 mutations that severely decrease microtubule dynamics do not prevent nuclear migration in yeast.

Microtubule dynamics are influenced by interactions of microtubules with cellular factors and by changes in the primary sequence of the tubulin molecule. Mutations of yeast beta-tubulin C354, which is located near the binding site of some antimitotic compounds, reduce microtubule dynamicity greater than 90% in vivo and in vitro. The resulting intrinsically stable microtubules allowed us to determine which, if any, cellular processes are dependent on dynamic microtubules. The average number of cytoplasmic microtubules decreased from 3 in wild-type to 1 in mutant cells. The single microtubule effectively located the bud site before bud emergence. Although spindles were positioned near the bud neck at the onset of anaphase, the mutant cells were deficient in preanaphase spindle alignment along the mother-bud axis. Spindle microtubule dynamics and spindle elongation rates were also severely depressed in the mutants. The pattern and extent of cytoplasmic microtubule dynamics modulation through the cell cycle may reveal the minimum dynamic properties required to support growth. The ability to alter intrinsic microtubule dynamics and determine the in vivo phenotype of cells expressing the mutant tubulin provides a critical advance in assessing the dynamic requirements of an essential gene function.

Cell Cycle↗
PubMed2001

Estrogen effects on neurite outgrowth and cytoskeletal gene expression in ERalpha-transfected PC12 cell lines.

The potential of gonadal steroids like estrogen (E) to promote neurite sprouting is of interest in development and aging, as well as after neural trauma. The specific roles of the two main estrogen receptors, ERalpha and ERbeta, in neuronal sprouting are not yet well understood. We examined the hypothesis that E can enhance nerve growth factor (NGF)-stimulated neurite sprouting in an ERalpha-dependent manner. PC12 cells that were stably transfected with the full-length rat ERalpha gene (PCER) and a control line of cells transfected with vector DNA alone (PCCON) were compared. Both cell lines vigorously differentiate neurites when treated with NGF. We determined that both lines show basal expression of ERbeta mRNA, but only the PCER cells express ERalpha mRNA. Estrogen treatment markedly enhanced NGF-stimulated neurite outgrowth from PCER but not from PCCON cells. Significantly larger proportions of PCER cells (34 and 53% at 24 and 48 h, respectively) had neurites than did the PCCON cells (17 and 26% at 24 and 48 h) after E plus NGF treatment. We also examined the effects of E and NGF treatment of PCER and PCCON cells on peripherin, alpha-tubulin, and tau mRNA expression. In undifferentiated PCER cells, E treatment increased peripherin, reduced alpha-tubulin, and did not alter tau mRNA levels. No changes in these mRNAs were observed in the controls (undifferentiated PCCON cells) after E treatment. NGF treatment markedly stimulated expression of peripherin, alpha-tubulin, and tau mRNAs in both PCER and PCCON cells. From these observations we conclude that E synergizes with NGF and stimulates neurite sprouting and also modulates expression of several cytoskeletal mRNAs through ERalpha.

Animals↗
PubMed2006

Chemoprotection by sulforaphane: keep one eye beyond Keap1.

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, with particularly high levels detected in broccoli and broccoli sprouts. Over a decade ago, this phytochemical was identified as a likely chemopreventive agent based on its ability to induce Phase 2 detoxification enzymes, as well as to inhibit Phase 1 enzymes involved in carcinogen activation. Considerable attention has focused on SFN as a 'blocking' agent, with the ability to modulate the Nrf2/Keap1 pathway, but recent evidence suggests that SFN acts by numerous other mechanisms. SFN induces cell cycle arrest and apoptosis in cancer cells, inhibits tubulin polymerization, activates checkpoint 2 kinase, and inhibits histone deacetylase activity. The latter findings suggest that SFN may be effective during the post-initiation stages of carcinogenesis, as a 'suppressing' agent. Moreover, pharmacological administration of SFN may be a promising therapeutic approach to the treatment of cancers, including those characterized by increased inflammation and involving viral or bacterial-related pathologies. The present review discusses the more widely established chemoprotective mechanisms of SFN, but makes the case for additional work on mechanisms that might be of importance during later stages of carcinogenesis, beyond Keap1.

Anticarcinogenic Agents↗
PubMed1999

Mechanisms of action of taxanes in prostate cancer.

Taxanes appear to have significant clinical activity in hormone-refractory prostate cancer and are entering increasing numbers of clinical trials. In general, they appear to initiate the apoptotic process by binding to beta-tubulin and promoting its polymerization. However, it is possible, at least in prostate cancer cell lines, that the ultimate decision for or against apoptosis may be modulated by a number of factors, including levels of Bcl-family members, especially the antiapoptotic proteins bcl-2 and bcl-xL. Differences in the cellular pharmacology of docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) and paclitaxel have been identified. Docetaxel has a somewhat higher affinity for microtubules than paclitaxel (approximately twofold), and in some circumstances may be a more potent inducer of bcl-2 phosphorylation. However, it is not clear whether these docetaxel-induced events are directly related to its antiprostate cancer effects. In murine macrophages, paclitaxel, but not docetaxel, induces several proinflammatory genes, but it is not known whether this occurs in prostate cancer cells. The mechanisms of cytotoxicity of taxanes in prostate cancer are undoubtedly complex and will require considerable additional study to fully understand.

Antineoplastic Agents, Hormonal↗