Anti-mitotic agents: Are they emerging molecules for cancer treatment?

Penna, Larissa Siqueira; Henriques, João Antônio Pêgas; Bonatto, Diego

doi:10.1016/j.pharmthera.2017.02.007

Cited by 64 publications

(67 citation statements)

References 287 publications

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“…Prolonged induction of the SAC is the means by which established, chemical microtubule poisons in cancer therapies such as vinca-alkaloids or taxanes work. Prolonged metaphase arrest often causes apoptotic cell death 20–22 . However, one major problem of such therapeutic interventions is that SAC activation and metaphase arrest are not permanent.…”

Section: Discussionmentioning

confidence: 99%

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

et al. 2018

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Tumor treating fields (TTFields) are approved for glioblastoma (GBM) therapy. TTFields disrupt cell division by inhibiting spindle fiber formation. Spindle assembly checkpoint (SAC) inhibition combined with antimitotic drugs synergistically decreases glioma cell growth in cell culture and mice. We hypothesized that SAC inhibition will increase TTFields efficacy. Human GBM cells (U-87 MG, GaMG) were treated with TTFields (200 kHz, 1.7 V/cm) and/or the SAC inhibitor MPS1-IN-3 (IN-3, 4 µM). Cells were counted after 24, 48, and 72 h of treatment and at 24 and 72 h after end of treatment (EOT). Flow cytometry, immunofluorescence microscopy, Annexin-V staining and TUNEL assay were used to detect alterations in cell cycle and apoptosis after 72 h of treatment. The TTFields/IN-3 combination decreased cell proliferation after 72 h compared to either treatment alone (−78.6% vs. TTFields, P = 0.0337; −52.6% vs. IN-3, P = 0.0205), and reduced the number of viable cells (62% less than seeded). There was a significant cell cycle shift from G1 to G2/M phase (P < 0.0001). The apoptotic rate increased to 44% (TTFields 14%, P = 0.0002; IN-3 4%, P < 0.0001). Cell growth recovered 24 h after EOT with TTFields and IN-3 alone, but the combination led to further decrease by 92% at 72 h EOT if IN-3 treatment was continued (P = 0.0288). The combination of TTFields and SAC inhibition led to earlier and prolonged effects that significantly augmented the efficacy of TTFields and highlights a potential new targeted multimodal treatment for GBM.

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Section: Discussionmentioning

confidence: 99%

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

et al. 2018

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“…These anticancer agents are broadly classified as alkylating agents, antimetabolites, antibiotics, natural products (e.g., colchicine and Taxol), and hormones. [6] Drugs that interfere with the polymerization and depolymerization of microtubules are called tubulin interactors. Based on their targets, anticancer agents are classified into tubulin and non-tubulin interactors.…”

Section: Introductionmentioning

confidence: 99%

“…Through these dynamic mechanisms, microtubules are one of the important components of cell division: they produce the mitotic spindle at anaphase to form new daughter cells. [6] Drugs that interfere with the polymerization and depolymerization of microtubules are called tubulin interactors. [7] Depending on their interference action, they are classified into two categories.…”

Section: Introductionmentioning

confidence: 99%

Upconverting Nanorockers for Intracellular Viscosity Measurements During Chemotherapy

et al. 2019

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molecules and organelles inside the cell. It is also a reliable indicator of the cellular state, which can be used to detect the appearance and onset of different diseases, including cancer. [1] The precise knowledge of the intracellular viscosity can be used to evaluate the effects caused by different treatments at the single-cell level. Indeed, cytoplasmic viscosity is modified when cancer cells are subjected to a chemotherapy process, so that variations in the intracellular viscosity can be used to assess the evolution of the treatment. [2] The intracellular environment is a composite of water and a variety of proteins and organelles. One of the main protein components of the cytoplasm is the cytoskeleton. This 3D network composed of filamentous proteins is a highly mobile, viscoelastic, and flexible entity that controls the cellular mechanics. [3] Particularly, alterations produced in the intracellular viscosity due to drug administration are governed by the effect of the chemical on the cytoskeleton of the cell. There are three major types of cytoskeletal filaments: microtubules, actin filaments, and intermediate filaments. They differ from each other in their molecular structure, function, and mechanical properties. These filamentous proteins, and other associated proteins, have Chemicals capable of producing structural and chemical changes on cells are used to treat diseases (e.g., cancer). Further development and optimization of chemotherapies require thorough knowledge of the effect of the chemical on the cellular structure and dynamics. This involves studying, in a noninvasive way, the properties of individual cells after drug administration. Intracellular viscosity is affected by chemical treatments and it can be reliably used to monitor chemotherapies at the cellular level. Here, cancer cell monitoring during chemotherapeutic treatments is demonstrated using intracellular allocated upconverting nanorockers. A simple analysis of the polarized visible emission of a single particle provides a real-time readout of its rocking dynamics that are directly correlated to the cytoplasmic viscosity. Numerical simulations and immunodetection are used to correlate the measured intracellular viscosity alterations to the changes produced in the cytoskeleton of cancer cells by anticancer drugs (colchicine and Taxol). This study evidences the possibility of monitoring cellular properties under an external chemical stimulus for the study and development of new treatments. Moreover, it provides the biomedical community with new tools to study intracellular dynamics and cell functioning.

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“…All such drugs are largely defined by their profound ability to compromise cellular dynamics during the crucial period of mitotic cell division and by so doing initiate apoptosis or autophagy related cell death [2]. As a reason of their success, traditional antimitotic agents like the vinca alkaloids have remained an integral part of anti-cancer agents available to clinicians since their first use about seven decades ago [3].…”

Section: Introductionmentioning

confidence: 99%

“…Their clinical effectiveness has encouraged the developments of newer therapeutics against several cellular and molecular targets involved in different stages of mitosis (e.g. microtubules, kinases, motor proteins, and multi-protein complexes) [2]. Importantly, those targeting the microtubules have been regarded as the most clinically effective [4].…”

Section: Introductionmentioning

confidence: 99%

Human MAP tau based targeted cytolytic fusion proteins

Akinrinmade

Jordaan

Hristodorov

et al. 2017

Preprint

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Some of the most promising small molecule toxins used to generate antibody drug conjugates (ADCs) include anti-mitotic agents (e.g auristatin and its derivatives) which are designed to attack cancerous cells at their most vulnerable state during mitosis. We were interested to identify a human cystostatic protein eventually showing comparable activities and allowing the generation of corresponding targeted fully human cytolytic fusion proteins. Recently, we identified the human microtubule associated protein tau (MAP tau) which binds specifically to tubulin and modulates the stability of microtubules thereby blocking mitosis and presumably vesicular transport. By binding and stabilizing polymerized microtubule filaments, MAP tau-based fusion proteins skew microtubule dynamics towards cell cycle arrest and apoptosis. This biological activity makes rapidly proliferating cells (e.g cancer and inflammatory cells) an excellent target for MAP tau-based targeted treatments. Their superior selectivity for proliferating cells confers additional selectivity towards upregulated tumor-associated antigens at their surface, thereby preventing off-target related toxicity against normal cells bearing tumor-associated antigens at physiologically normal to low levels. In this review, we highlight recent findings on MAP tau-based targeted cytolytic fusion proteins reported in preclinical immunotherapeutic studies.

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Anti-mitotic agents: Are they emerging molecules for cancer treatment?

Cited by 64 publications

References 287 publications

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

Upconverting Nanorockers for Intracellular Viscosity Measurements During Chemotherapy

Human MAP tau based targeted cytolytic fusion proteins

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