Plinabulin, an inhibitor of tubulin polymerization, targets KRAS signaling through disruption of endosomal recycling.

Constitutive activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic event in certain types of human cancer and is associated with poor patient survival. Small molecule signaling inhibitors have improved the clinical outcomes of patients with various cancer types but attempts to target KRAS have been unsuccessful. Plinabulin represents a novel class of agents that inhibit tubulin polymerization with a favorable safety profile in clinical trials.

Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs.

βIII-tubulin enhances efficacy of cabazitaxel as compared with docetaxel.

Cabazitaxel is a novel taxane approved for treatment of metastatic hormone-refractory prostate cancer in patients pretreated with docetaxel. Cabazitaxel, docetaxel, and paclitaxel bind specifically to tubulin in microtubules, disrupting functions essential to tumor growth. High levels of βIII-tubulin isotype expression are associated with tumor aggressivity and drug resistance.

Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment with microtubule-targeted agents (MTAs). The frequency of severe CIPN, which can be dose limiting and even life threatening, varies widely among different MTAs. For example, paclitaxel induces a higher frequency of severe CIPN than does eribulin.

Effects of Paclitaxel and Eribulin in Mouse Sciatic Nerve: A Microtubule-Based Rationale for the Differential Induction of Chemotherapy-Induced Peripheral Neuropathy.

Microtubule targeting agents (MTAs) often lead to treatment limiting and life threatening side effects, including chemotherapy-induced peripheral neuropathy (CIPN). The frequency of severe CIPN varies among different MTAs. Since the microtubule binding interactions and mechanisms of action also vary among MTAs, we hypothesized that these distinct mechanisms may underlie the variability in frequency of severe CIPN.

Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype.

Eribulin mesylate (Halaven) is a microtubule-targeted anticancer drug used to treat patients with metastatic breast cancer who have previously received a taxane and an anthracycline. It binds at the plus ends of microtubules and has been shown to suppress plus end growth selectively. Because the class III β tubulin isotype is associated with resistance to microtubule targeting drugs, we sought to determine how βIII tubulin might mechanistically influence the effects of eribulin on microtubules.

Mechanism of action of ixabepilone and its interactions with the βIII-tubulin isotype.

Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. Ixabepilone's binding and mechanism of action on microtubules and their dynamics, as well as its interactions with isotypically altered microtubules, both in vitro and in tumor cells, have not been described. Microtubules are dynamic polymers of the protein tubulin that function in mitosis, intracellular transport, cell proliferation, and migration.

Erucin, the major isothiocyanate in arugula (Eruca sativa), inhibits proliferation of MCF7 tumor cells by suppressing microtubule dynamics.

Consumption of cruciferous vegetables is associated with reduced risk of various types of cancer. Isothiocyanates including sulforaphane and erucin are believed to be responsible for this activity. Erucin [1-isothiocyanato-4-(methylthio)butane], which is metabolically and structurally related to sulforaphane, is present in large quantities in arugula (Eruca sativa, Mill.

The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation.

Background: Microtubule stabilizers suppress microtubule dynamics and, at the lowest antiproliferative concentrations, disrupt the function of mitotic spindles, leading to mitotic arrest and apoptosis. At slightly higher concentrations, these agents cause the formation of multiple mitotic asters with distinct morphologies elicited by different microtubule stabilizers.

Results: We tested the hypothesis that two classes of microtubule stabilizing drugs, the taxanes and the taccalonolides, cause the formation of distinct aster structures due, in part, to differential effects on microtubule dynamics.

Mechanisms of inhibition of endothelial cell migration by taxanes.

Several antiangiogenic mechanisms have been proposed for the widely-used cancer chemotherapeutic drugs taxotere (docetaxel) and taxol (paclitaxel), but none has been definitively identified. We analyzed their effects at a range of concentrations on migration and mitosis of human umbilical vein endothelial cells (HUVECs) on microtubule and focal adhesion morphology and microtubule dynamic instability during migration. Both taxanes inhibited migration by inhibiting both maintenance of the forward direction of the cell and by slowing migration over the entire contorted path length.

Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious, painful and dose-limiting side effect of cancer drugs that target microtubules. The mechanisms underlying the neuronal damage are unknown, but may include disruption of fast axonal transport, an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals. This idea is supported by the "dying back" pattern of degeneration observed in CIPN, and by the selective vulnerability of sensory neurons bearing the longest axonal projections.

Modeling the effects of drug binding on the dynamic instability of microtubules.

We propose a stochastic model that accounts for the growth, catastrophe and rescue processes of steady-state microtubules assembled from MAP-free tubulin in the possible presence of a microtubule-associated drug. As an example of the latter, we both experimentally and theoretically study the perturbation of microtubule dynamic instability by S-methyl-D-DM1, a synthetic derivative of the microtubule-targeted agent maytansine and a potential anticancer agent. Our model predicts that among the drugs that act locally at the microtubule tip, primary inhibition of the loss of GDP tubulin results in stronger damping of microtubule dynamics than inhibition of GTP tubulin addition.

Combinatorial Tau pseudophosphorylation: markedly different regulatory effects on microtubule assembly and dynamic instability than the sum of the individual parts.

Tau is a multiply phosphorylated protein that is essential for the development and maintenance of the nervous system. Errors in Tau action are associated with Alzheimer disease and related dementias. A huge literature has led to the widely held notion that aberrant Tau hyperphosphorylation is central to these disorders.

Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability.

Maytansine and its analogues (maytansinoids) are potent microtubule-targeted compounds that inhibit proliferation of cells at mitosis. Antibody-maytansinoid conjugates consisting of maytansinoids (DM1 and DM4) attached to tumor-specific antibodies have shown promising clinical results. To determine the mechanism by which the antibody-DM1 conjugates inhibit cell proliferation, we examined the effects of the cleavable anti-EpCAM-SPP-DM1 and uncleavable anti-EpCAM-SMCC-DM1 conjugates on MCF7 human breast tumor cells.

Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules.

Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at subnanomolar concentrations. However, its side effects and lack of tumor specificity have prevented successful clinical use. Recently, antibody-conjugated maytansine derivatives have been developed to overcome these drawbacks.

Microtubule-binding agents: a dynamic field of cancer therapeutics.

Microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. Agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to DNA as a therapeutic target in cancer. The screening of a range of botanical species and marine organisms has yielded promising new antitubulin agents with novel properties.

Characterization and detection of cellular and proteomic alterations in stable stathmin-overexpressing, taxol-resistant BT549 breast cancer cells using offgel IEF/PAGE difference gel electrophoresis.

Stathmin/oncoprotein 18, a protein that regulates microtubule dynamics, is highly expressed in a number of tumors including leukemia, lymphoma, neuroblastoma, breast, ovarian, and prostate cancers. High stathmin levels have been associated with the development of resistance to the widely used anti-cancer drug taxol ((®)Taxol, paclitaxel). The mechanisms of stathmin-mediated taxol resistance are not well-understood at the molecular level.

Determination of microtubule dynamic instability in living cells.

The precise regulation of microtubules and their dynamics is critical for cell cycle progression, cell signaling, intracellular transport, cell polarization, and organismal development. For example, mitosis, cell migration, and axonal outgrowth all involve rapid and dramatic changes in microtubule organization and dynamics. Microtubule-associated proteins (MAPs) such as MAP2 and tau (Bunker et al.

Determination of drug binding to microtubules in vitro.

Many naturally occurring compounds and their synthetic analogs bind to soluble tubulin or to tubulin in microtubules. These compounds are often important drugs or drug candidates. They can potently alter both the dynamics and the polymer mass of microtubules.

Microtubule dynamics, mitotic arrest, and apoptosis: drug-induced differential effects of betaIII-tubulin.

Overexpression of betaIII-tubulin is associated with resistance to tubulin-binding agents (TBA) in a range of tumor types. We previously showed that small interfering RNA silencing of betaIII-tubulin expression hypersensitized non-small cell lung cancer cells to TBAs. To determine whether betaIII-tubulin mediates its effect on drug-induced mitotic arrest and cell death by differentially regulating microtubule behavior, the effects of betaIII-tubulin knockdown on microtubule dynamics were analyzed in H460 non-small cell lung cancer cells stably expressing green fluorescent protein-betaI-tubulin.

The neuroprotective peptide NAP does not directly affect polymerization or dynamics of reconstituted neural microtubules.

NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is a neuroprotective peptide that shows cognitive protection in patients with amnestic mild cognitive impairment, a precursor to Alzheimer's disease. NAP exhibits potent neuroprotective properties in several in vivo and cellular models of neural injury. While NAP has been found in many studies to affect microtubule assembly and/or stability in neuronal and glial cells at fM concentrations, it has remained unclear whether NAP acts directly or indirectly on tubulin or microtubules.

Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability.

Eribulin mesylate (E7389), a synthetic analogue of the marine natural product halichondrin B, is in phase III clinical trials for the treatment of cancer. Eribulin targets microtubules, suppressing dynamic instability at microtubule plus ends through an inhibition of microtubule growth with little or no effect on shortening [Jordan, M. A.