Microtubule-Targeting Drugs: More than Antimitotics - Journal of

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Microtubule-Targeting Drugs: More than Antimitotics Roma Kaul,† April L. Risinger,†,‡ and Susan L. Mooberry*,†,‡ Department of Pharmacology and ‡Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States

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ABSTRACT: Nature has yielded numerous compounds that bind to tubulin/microtubules and disrupt microtubule function. Even with the advent of targeted therapies for cancer, natural products and their derivatives that target microtubules are some of the most effective drugs used in the treatment of solid tumors and hematological malignancies. For decades, these drugs were thought to work solely through their ability to inhibit mitosis. Accumulating evidence demonstrates that their actions are much more complex, in that they also have significant effects on microtubules in nondividing cells that inhibit a diverse range of signaling events important for carcinogenesis. The abilities of these drugs to inhibit oncogenic signaling likely underlies their efficacy, especially in solid tumors. In this review, we describe the role of microtubules in cells, the proliferation paradox of cells in culture as compared to cancers in patients, and evidence that microtubule-targeting drugs inhibit cellular signaling pathways important for tumorigenesis. The potential mechanisms behind differences in the clinical indications and efficacy of these natural-product-derived drugs are also discussed. Microtubules are an important target for structurally diverse natural products, and a fuller understanding of the mechanisms of action of these drugs will promote their optimal use.

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advancing.9−15 Herein, we present this evidence for the natural products community, because microtubule-targeting compounds are found throughout Nature and the continued discovery and development of new MTAs with subtly different mechanisms of action will continue to be a worthwhile endeavor.

INTRODUCTION Natural products from diverse source organisms continue to provide the majority of drug leads for many diseases, including cancer.1−3 A wide variety of tubulin/microtubule-targeting compounds with diverse chemical structures have been isolated from marine and terrestrial organisms including higher plants, marine sponges and mollusks, cyanobacteria, myxobacteria, and endophytic bacteria.4−6 These secondary metabolites bind directly to tubulin/microtubules and disrupt cellular microtubule structure and function. A subset of these natural products and their derivatives have found significant utility in the treatment of cancer, and these drugs are the topic of this review. All of the FDA-approved microtubule targeting agents (MTAs) are natural products or derivatives of compounds first identified in Nature,5−7 and they are highly effective drugs used for the treatment of solid tumors and hematological malignancies. While the advent of targeted cancer therapies has been a major advance in cancer treatment, it is important to recognize that they are often used most successfully in combination with a variety of traditional small-molecule cytotoxic chemotherapies, including MTAs.8 Additionally, clinical responses of patients have shown that one MTA can be effective following the failure of another, suggesting that a fuller understanding of the mechanisms of action and differences among MTAs could result in better patient outcomes. Over the past decade, accumulating evidence suggests that MTAs have many actions independent of their effects on mitosis, and the concept that they are more than antimitotics has been © XXXX American Chemical Society and American Society of Pharmacognosy

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MICROTUBULES AND MICROTUBULE-TARGETING AGENTS Microtubules are an integral part of the cytoskeleton, and they are critical for multiple aspects of cellular function, including the intracellular transport of vesicles, proteins, and organelles. Microtubules also play important roles in cell migration, maintaining cell shape and polarity, compartmentalizing the cytoplasm, and orchestrating mitosis.16−20 Microtubules are tubular structures composed of polymers of αβ-tubulin heterodimers that form from the lateral association of (typically) 13 protofilaments (Figure 1). Microtubules are polarized structures, with minus- and plus-ends defined by their “head-to-tail” assembly from αβ-tubulin. The β-tubulin subunit is exposed at the more dynamic plus-end of the microtubule, which typically extends toward the cell periphery.21 The microtubule minus-end is less dynamic and, Special Issue: Special Issue in Honor of Drs. Rachel Mata and Barbara Timmermann Received: February 4, 2019

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Figure 1. Structure of microtubules: αβ-tubulin heterodimers assemble into protofilaments, which form microtubules by lateral association resulting, typically, in a microtubule with 13 protofilaments. Microtubules have polarity with the minus-ends nucleating at the microtubuleorganizing center (MTOC) and plus-ends extending to the cell periphery.

tubule destabilizers with significant antitumor effects, including the cryptophycins and tubulysins, are also being evaluated as ADC payloads.31,32 Paclitaxel, the first microtubule stabilizer identified,33−35 was approved for clinical use by the FDA in the 1990s.36,37 Secondand third-generation taxanes including docetaxel, cabazitaxel, and nab-paclitaxel have found significant clinical utility. The success of the taxanes led to intense efforts to discover additional microtubule stabilizers, and the first new class identified was the epothilones, macrolides isolated from cultures of the myxobacterium Sporangium cellulosum.38 The epothilone B analogue ixabepilone was approved for use in metastatic breast cancer in 2007. The first marine-derived MTA, discodermolide, is a microtubule stabilizer that failed in phase I clinical testing due to lung toxicities.7 However, discodermolide−paclitaxel hybrid congeners with promising activities are being developed.39 Despite the large number and structural diversity of MTAs, relatively few microtubule/tubulin-binding sites have been identified.40 The taxane site on the interior of the microtubule is where most microtubule stabilizers bind, including all clinically approved stabilizers. Clinically approved MTAs that bind within this site include paclitaxel, docetaxel, cabazitaxel, and ixabepilone.5 Compounds that bind covalently within the taxane site include the taccalonolides, zampanolides, and cyclostreptin.41−43 While they are not in clinical use, their covalent binding mode makes them attractive for targeted delivery. The only other microtubule stabilizer site is the laulimalide/peloruside site located on the exterior of the microtubule,44 and it has yet to yield a clinical candidate due to multiple challenges, including lack of preclinical activity for laulimalide45 and supply challenges for peloruside.46 Four tubulin-binding sites have been identified for microtubule depolymerizers: the vinca site,47 the colchicine site,26 the maytansine site,48 and, more recently, the pironetin site.49,50 Most microtubule-depolymerizing anticancer drugs, including the vinca alkaloids and eribulin, bind within the vinca domain of tubulin. The vinca alkaloids bind to β-tubulin, but eribulin binds exclusively at the plus-end of the microtubule overlapping with only half the site engaged by vinca alkaloids.7,51,52 The colchicine-binding site is located on βtubulin at the intradimer interface of α- and β-tubulin subunits.7,40 The maytansine site is also on β-tubulin, in close proximity but nonoverlapping with the vinca site.48 In contrast, the newly identified pironetin site is on α-tubulin.49,50

in cells, is commonly anchored at the centrosome-containing microtubule organizing center (MTOC) adjacent to the nucleus.22 Microtubules are highly dynamic and constantly alternate between phases of growing and shrinking in response to changing cellular needs. While microtubules have intrinsic dynamic properties due to the hydrolysis of GTP in the exchangeable site on β-tubulin, microtubule dynamics are additionally facilitated by a wide range of cellular factors, including plus-end tip binding proteins, tubulin post-translational modifications, and the expression of different tubulin isotypes.21,23 The microtubule network is indispensable for maintaining a myriad of critical cellular functions, and its roles are nonredundant with other cellular structures in that other cellular components cannot duplicate the diverse functions of microtubules. The abilities of MTAs to interrupt these functions is important to their anticancer efficacies and will be discussed below. MTAs are categorized into two major groups: (a) microtubule destabilizers that initiate microtubule depolymerization, leading to microtubule disassembly and a decrease in microtubule density, and (b) microtubule stabilizers that promote the polymerization of tubulin, thereby increasing the density of microtubules. Colchicine, the first MTA to be identified, is a destabilizing MTA isolated from Colchicum autumnale L. in the 1800s and subsequently identified as having tubulin-binding properties in the 1940s.24−26 Although colchicine does not have an acceptable therapeutic window for the treatment of cancer, its isolation paved the way for the identification of other MTAs. In the 1950s, the vinca-alkaloiddestabilizing MTAs were isolated from the leaves of Catharanthus roseus (L.) G. Don, and vinblastine and vincristine were approved as anticancer chemotherapeutic drugs in the 1960s.27,28 Third-generation semisynthetic vinca alkaloids, vinorelbine, vindesine, and vinflunine, were later approved for the treatment of solid tumors and hematological malignancies.7 More recently, clinical success of a microtubuledestabilizing MTA was obtained with eribulin, a simplified synthetic analogue of the polyether macrolide sponge natural product halichrondrin B.29 Potent microtubule destabilizers including the dolastatin 10 analogue, monomethyl auristatin E, and maytansine analogues have also recently proven to be useful as the cytotoxic payloads of antibody−drug conjugates (ADCs).30 While these unconjugated MTAs were too toxic for systemic administration, their antibody-directed delivery to cancers reduces off-target toxicities.30 Other potent microB

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companies extended from the preclinical stages to clinical trials, at a total cost exceeding $10 billion USD.9 While these agents had excellent preclinical activities, inhibiting mitosis in vitro and in murine models of cancer, they were ineffective clinically, with an average clinical response rate in solid tumors of only 1.6%.10,60 The poor clinical efficacy of drugs that inhibit mitosis independent of microtubule binding further calls into question the long-held view that the anticancer efficacy of MTAs can be attributed solely to their antimitotic effects.9,10 What Is the Evidence That MTAs Have Nonmitotic Effects? High-resolution intravital microscopy combined with elegant molecular biology tools allows real-time evaluation of cell cycle progression and apoptosis in murine tumors.61−63 Orth et al. measured a maximal mitotic index of only 7% in tumors in mice 24 h following paclitaxel administration, a modest increase of the mitotic index over untreated controls.61 While a significant accumulation of cells in mitosis was not observed, this dose of paclitaxel was highly effective, resulting in an 80% reduction in tumor size as compared to controls at 2 weeks.61 Another study with docetaxel reported similar findings in different tumor types.62 While the effects of docetaxel in tissue culture were dependent on mitosis, in murine tumors, 93% of cancer cells initiated apoptosis independent of mitotic defects.62 Chittajallu and colleagues evaluated the pharmacodynamics of paclitaxel and eribulin in a fibrosarcoma xenograft model over 8 days and quantified the number of cells in each phase of the cell cycle over this time. Following drug administration, a modest, 3−20%, increase of cells in mitosis was measured, coincident with a decrease in cell density over this time, which is consistent with the antitumor effects of these drugs.63 These authors each concluded that their experiments provide evidence that the antitumor efficacy of MTAs involves more than inhibition of mitosis. While the predominant effects of MTAs in cancer cells in culture is disruption of mitosis, evidence of the nonmitotic effects of MTAs has also been observed in these models. Cells in culture have different doubling times, and rate of cell proliferation does not correlate with sensitivity to MTAs.64 This suggests that the efficacy of MTAs does not depend entirely on the frequency of mitosis, invoking nonmitotic events. Vinorelbine caused ∼90% of colorectal cancer cells with APC mutations to die independent of mitosis.65 The loss of APC in these cells resulted in a dysfunctional mitotic checkpoint, in that they could not arrest in mitosis, thus uncovering the nonmitotic effects of vinorelbine. In other studies, leukemia cells in the G1 phase of the cell cycle initiated apoptosis in response to vincristine or eribulin without first transitioning to mitosis.66,67 This interphase apoptosis occurred with drug concentrations greater than 100 nM, a concentration known to cause complete microtubule depolymerization.68 Together, these studies demonstrate that MTAs can initiate apoptosis independent of mitosis, even in cancer cells in culture. An important piece of evidence demonstrating that MTAs can elicit nonmitotic effects is the observation that one of their most prevalent dose-limiting toxicities is the initiation of peripheral neuropathy, which is a result of damage to nondividing neuronal cells.69 The ability of MTAs to inhibit the axonal transport of cellular cargo, including neurotransmitters and mitochondria, along axonal microtubules is thought to contribute to this neuropathy.70 Peripheral nerves

In summary, the last 50 years have witnessed the isolation, identification, and clinical evaluation of a number of MTAs, resulting in several highly effective anticancer drugs.6,7 As a result of the clinical success of MTAs, new agents in this class of drugs continue to be identified and advanced into clinical trials.53

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MECHANISM OF ACTION INVOLVES MORE THAN INHIBITION OF MITOSIS As discussed above, microtubules have important functions in all phases of the cell cycle, from interphase to mitosis.16,19 While microtubules are dynamic during interphase, during mitosis their rate of dynamicity increases 4−100-fold.54,55 This high rate of dynamicity is necessary for the mitotic spindles to coordinate binding to the kinetochores of each chromosome, align them across the equatorial plane of the cell, and generate the required tension to separate sister chromatids to daughter cells with high fidelity. MTA-induced disruption of microtubule dynamics causes mitotic arrest in cancer cells in vitro within 8−24 h due to their failure to properly segregate chromosomes to daughter cells, ultimately leading to apoptosis. The antimitotic effects of MTAs are typically studied in vitro using cancer cell lines that have been selected for their ability to proliferate rapidly, with doubling times on the order of 24−48 h.56,57 Exposure of these rapidly proliferating cells to MTAs results in the formation of aberrant mitotic spindles and accumulation of the vast majority of cells in the G2/M phase of the cell cycle within 24 h. These antimitotic effects are dramatic and have been the dominant in vitro phenotype observed for MTAs, leading to this class of drugs also being referred to simply as “antimitotics”. Even in xenograft and syngeneic animal tumor models, cancer cells typically divide once every 10−12 days,9 which allows for the evaluation of antitumor effects within a relatively short time period. In these rapidly dividing in vitro and in vivo cancer models, it is likely that the efficacy of MTAs is primarily due to their antimitotic effects that ultimately lead to apoptosis.9 While there is no doubt that MTAs can cause cell death as a result of their antimitotic effects, there is a common misconception that cancer cells in patients divide as rapidly as in these preclinical models, which is not the case. Solid tumors in human patients divide much less frequently with a rate of cell division ranging from ∼150 to 300 days.9−11 Thus, solid tumors in patients double every 5−10 months, much slower than the doubling rate of cancer cells in vitro or in murine models. The fact that cancer cells in patients proceed through a mitotic event much less often than preclinical models is supported by a mitotic index of less than 1% in solid tumors, and this is not affected by MTA administration.58,59 These results provide evidence that mitosis is a rare event in human solid tumors and that mitotic inhibition is likely not the sole anticancer mechanism of MTAs. Targeting Mitosis. Mitosis is regulated by the coordinated action of microtubules together with mitotic kinases and other regulatory proteins, including mitotic kinesins. The clinical successes of MTAs combined with their antimitotic effects in preclinical models prompted the development and clinical evaluation of a number of drugs that inhibit mitotic kinases or kinesins. The rationale was that these drugs would have the anticancer efficacy of MTAs without their significant tubulinrelated toxicities. Extensive efforts were employed to develop over 20 non-tubulin-binding antimitotic agents. These drug development programs conducted by major pharmaceutical C

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drug- or radiation-induced DNA damage, providing a rationale for the efficacy of combining an MTA with a DNA-damaging agent. Other important oncogenic signaling pathways that require microtubules and have been shown to be disrupted by MTAs include EGFR-mediated growth factor signaling,85 HIF-1αmediated angiogenesis,86,87 and key drivers of the epithelial-tomesenchymal transition (EMT) associated with invasion and metastasis.88 In particular, a 7-day treatment with eribulin reversed EMT-associated phenotypes in breast cancer cells.88 The ability of eribulin to rapidly promote cortical E-cadherin localization,68 an important mediator of the epithelial phenotype, might contribute to its ability to reverse EMT in preclinical models and in patients.88,89 In breast cancer cells, eribulin and vinorelbine inhibit TGF-β-induced activation of the EMT-promoting transcription factor Snail, as a downstream consequence of inhibiting the nuclear translocation of Smad2/3, within only a few hours of MTA treatment.90 Interestingly, paclitaxel had no effect on Snail transcription.90 The fact that these signaling consequences are observed within hours of MTA addition further supports that these drugs interrupt oncogenic signaling pathways independent of mitotic accumulation.

are presumably most sensitive to MTAs due to their long axons that depend on efficient microtubule-depending trafficking. The differential effects of MTAs on the tumor vasculature is another indication that their actions are much more complex than initially appreciated. Combretastatin A-4 and other colchicine-site MTAs induce destruction of tumor vasculature in murine cancer models within 1 h, resulting in loss of perfusion to the central tumor regions.71 This led to the development of multiple colchicine-site vascular disrupting agents, and even in patients, combretastatin A-4 phosphatemediated disruption in tumor vasculature was observed.72 In stark contrast, eribulin remodels and effectively stabilizes tumor vasculature in murine models, leading to improved perfusion of the interior of the tumor.73 Increased tumor oxygen saturation was measured in patients treated with eribulin, supporting these preclinical findings.74 These rapid and divergent effects of different classes of microtubuledestabilizing agents on the tumor vasculature cannot be explained by mitotic disruption. What Underlies the Anticancer Efficacy of MTAs? To appreciate the nonmitotic mechanisms of action of MTAs in cancer, it is valuable to review the functions of microtubules in nondividing cells. Microtubules have essential roles in cellular signaling, both as a conduit for the intracellular trafficking of proteins20 and for their ability to serve as cellular scaffolds that facilitate protein−protein interactions.75−77 Cancer cell survival, proliferation, and metastasis are driven by oncogenic signaling pathways that rely on functional interphase microtubules; therefore, MTA-mediated disruption of microtubule dynamics and structure in cancer cells can have catastrophic consequences for oncogenic signaling.12 Some examples of the abilities of MTAs to impact oncogenic signaling are androgen signaling in prostate cancer cells and transport of DNA repair proteins in response to DNA damage. These and other pathways impacted by MTAs are described in detail below. Prostate cancer is sustained by androgen signaling, and inhibition of androgen receptor (AR) function remains the primary target for therapy.78 The androgen receptor traffics from the plasma membrane to the nucleus upon ligand activation in a microtubule-dependent manner to initiate expression of androgen-responsive genes. Treatment of prostate cancer cells with paclitaxel inhibits AR nuclear localization and transcriptional activity.79−81 In further studies, impaired AR nuclear transport in circulating tumor cells predicted patient response to docetaxel.79 Additionally, splice variants in AR that disrupt microtubule binding are resistant to taxanes in vitro and in vivo, demonstrating a direct role of microtubule-dependent AR trafficking in the antitumor effects of the taxanes.82 MTAs are often effectively combined with DNA-damaging drugs, and recent evidence provides a mechanistic framework for this combination.83,84 DNA damage promotes the nuclear localization of DNA repair proteins, which traffic to the nucleus in a microtubule-dependent manner. Vincristine and paclitaxel impaired the dynein-mediated nuclear transport of DNA repair proteins along the microtubule in lung and ovarian cancer cells following DNA damage.83 Additionally, the treatment of glioma cells for 3−9 h with an MTA was found to sensitize them to ionizing radiation exclusively during interphase by inhibiting the nuclear translocation of DNA repair proteins.84 Together these data demonstrate that the ability of MTAs to inhibit microtubule-mediated transport of DNA repair proteins impairs the ability of cancer cells to repair

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MTAS ARE NOT EQUAL As we begin to appreciate the diverse mechanisms of action of MTAs, it is important not to overlook differences among drugs. Basic research is beginning to provide mechanistic clues to explain clinical differences among MTAs. MTAs can be distinguished based on their effects on microtubule dynamics and structure. Intriguingly, there are even biochemical differences between paclitaxel and docetaxel, drugs that bind within the same site on microtubules, which could underlie differences in their clinical activities. X-ray scattering profiles of microtubules assembled from purified tubulin show that docetaxel-induced microtubules have on average 13.4 protofilaments, while paclitaxel-induced microtubules have on average 12 protofilaments.91 Differences in their clinical activities were noted early in the development of docetaxel,92 and patients refractory to paclitaxel can respond to docetaxel and ixabepilone, drugs that all bind within the taxane site.93,94 It is interesting to speculate that the distinct allosteric effects of these drugs on microtubules differentially impact microtubuledependent transport, resulting in subtly different effects on oncogenic signaling. These studies encourage further efforts to identify differences among MTAs that can inform on their optimal use.

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CONCLUSION Microtubule-targeting drugs remain some of the most effective anticancer agents; however, their historic classification as antimitotics does not fully describe their function. MTAs are likely successful due, at least in part, to their abilities to disrupt multiple oncogenic processes in interphase cells, effects that are not yet completely understood. Continued efforts to identify the diverse effects of MTAs on oncogenic signaling pathways will provide opportunities to use these drugs in a more rational manner.95 Additionally, a more detailed understanding of the specific effects individual MTAs have on oncogenic signaling pathways could enable the identification of biomarkers to help guide therapy. Furthermore, identifying novel MTAs with even slightly different binding D

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modes could lead to the development of agents with distinct profiles of activity and increased clinical efficacy. Because microtubule-active agents are found throughout Nature, the natural products community remains at the forefront of discovering bioactive compounds with unique microtubulebinding properties that could have therapeutic advantages.

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AUTHOR INFORMATION

Corresponding Author

*Tel: (210) 567-4788. E-mail: [email protected]. ORCID

Roma Kaul: 0000-0002-1135-5208 April L. Risinger: 0000-0002-4363-3268 Notes

The authors declare the following competing financial interest(s): Funding was provided by Eisai Inc.

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ACKNOWLEDGMENTS Funding was provided by Eisai Inc. We thank Dr. Robert Cichewicz for his helpful suggestions. DEDICATION Dedicated to Dr. Rachel Mata, National Autonomous University of Mexico, Mexico City, Mexico, and Dr. Barbara N. Timmermann, University of Kansas, for their pioneering work on bioactive natural products.

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REFERENCES

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Journal of Natural Products

Review

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DOI: 10.1021/acs.jnatprod.9b00105 J. Nat. Prod. XXXX, XXX, XXX−XXX