Low-Dose Eribulin Promotes NK Cell-Mediated Therapeutic Efficacy in Bladder Cancer.

Unlabelled: Despite its immunogenic nature, bladder cancer (BCa) responds sub-optimally to FDA-approved immunotherapy.

Background/objectives: We have previously shown that natural killer (NK) cells are major contributors to overall patient survival in BCa. In our efforts to identify clinically approved agents that enhance NK cell activation, we identified eribulin, a microtubule destabilizer primarily used in breast cancer.

Chemical Diversity of Aspergillus alliaceus Phenotypes: Discovery of Brominated Bianthrones with Activity against Triple-Negative Breast Cancer Cell Lines.

Marine-derived fungi have emerged as a source for novel metabolites with a broad range of bioactivities. However, accessing the full potential of fungi under standard laboratory conditions remains challenging. LC-MS-based metabolomics in combination with varied culture conditions is a fast and powerful tool to detect new metabolites.

The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models.

Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials.

In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site.

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (-)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy.

One- and Two-Photon Activated Release of Oxaliplatin from a Pt(IV)-Functionalized Poly(phenylene ethynylene).

We report a water-soluble poly(phenylene ethynylene) () that is functionalized with oxidized oxaliplatin Pt(IV) units and its use for photoactivated chemotherapy. The photoactivation strategy is based on photoinduced electron transfer from the PPE backbone to oxaliplatin Pt(IV) as an electron acceptor; this process triggers the release of oxaliplatin, which is a clinically used anticancer drug. Mechanistic studies carried out using steady-state and time-resolved fluorescence spectroscopy coupled with picosecond-nanosecond transient absorption support the hypothesis that electron transfer triggers the drug release.

Re-evaluation of the Fijianolide/Laulimalide Chemotype Suggests an Alternate Mechanism of Action for C-15/C-20 Analogs.

Herein, we report on naturally derived microtubule stabilizers with activity against triple negative breast cancer (TNBC) cell lines, including paclitaxel, fijianolide B/laulimalide (), fijianolide B di-acetate (), and two new semisynthetic analogs of , which include fijianolide J () and fijianolide L (). Similar to paclitaxel, compound demonstrated classic microtubule stabilizing activity with potent (GI = 0.7-17 nM) antiproliferative efficacy among the five molecularly distinct TNBC cell lines.

Altertoxin II, a Highly Effective and Specific Compound against Ewing Sarcoma.

A screening program designed to identify natural products with selective cytotoxic effects against cell lines representing different types of pediatric solid tumors led to the identification of altertoxin II as a highly potent and selective cytotoxin against Ewing sarcoma cell lines. Altertoxin II, but not the related compounds altertoxin I and alteichin, was highly effective against every Ewing sarcoma cell line tested, with an average 25-fold selectivity for these cells as compared to cells representing other pediatric and adult cancers. Mechanism of action studies revealed that altertoxin II causes DNA double-strand breaks, a rapid DNA damage response, and cell cycle accumulation in the S phase.

Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA.

Microtubule-targeting agents (MTAs), including both microtubule stabilizers and destabilizers are highly effective chemotherapeutic drugs used in the treatment of solid tumors and hematologic malignancies. In addition to the shared ability of all MTAs to block cell cycle progression, growing evidence shows that different agents of this class can also have mechanistically distinct effects on nonmitotic microtubule-dependent cellular processes, including cellular signaling and transport. Herein, we test the biologic hypothesis that MTAs used in the treatment of triple-negative breast cancer (TNBC) can differentially affect innate immune signaling pathways independent of their antimitotic effects.

Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models.

Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds β-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement.

Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential.

The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity.

Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities.

The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to β-tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve target engagement. Most notably, modification of C-6 on the taccalonolide backbone with the C-13 -acyl-β-phenylisoserine side chain of paclitaxel provided compounds with 10-fold improved potency for biochemical tubulin polymerization as compared to that of the unmodified epoxy taccalonolide AJ.

Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization.

Synthesis and Biological Evaluations of Electrophilic Steroids Inspired by the Taccalonolides.

Natural products have served as inspirational scaffolds for the design and synthesis of novel antineoplastic agents. Here we present our preliminary efforts on the synthesis and biological evaluation of a new class of electrophilic steroids inspired by the naturally occurring taccalonolides. We demonstrate that these simplified analogs exhibit highly persistent antiproliferative properties similar to the taccalonolides and retain activity against resistant cancer cell lines that warrants further preclinical development.

Taccalonolide Microtubule Stabilizers.

Microtubule stabilizers are a mainstay in the treatment of many solid cancers and continue to find utility in combination therapy with molecularly targeted anticancer agents and immunotherapeutics. However, innate and acquired resistance to microtubule stabilizers can limit their clinical efficacy. The taccalonolides are a unique class of microtubule stabilizers isolated from plants of Tacca that circumvent clinically relevant mechanisms of drug resistance.

CRISPR-Cas9 Genome-Wide Knockout Screen Identifies Mechanism of Selective Activity of Dehydrofalcarinol in Mesenchymal Stem-like Triple-Negative Breast Cancer Cells.

There are no targeted therapies available for triple-negative breast cancers (TNBCs) in part because they represent a heterogeneous group of tumors with diverse oncogenic drivers. Our goal is to identify targeted therapies for subtypes of these cancers using a mechanism-blind screen of natural product extract libraries. An extract from was 4-fold more potent for cytotoxicity against MDA-MB-231 cells, which represent the mesenchymal stem-like (MSL) subtype, as compared to cells of other TNBC subtypes.

Triple-Negative Breast Cancer Cells Exhibit Differential Sensitivity to Cardenolides from .

Triple-negative breast cancers (TNBC) are aggressive and heterogeneous cancers that lack targeted therapies. We implemented a screening program to identify new leads for subgroups of TNBC using diverse cell lines with different molecular drivers. Through this program, we identified an extract from that caused selective cytotoxicity in BT-549 cells as compared to four other TNBC cell lines.

Leucinostatins from spp. and spp. Demonstrate Selective Antiproliferative Effects in Cells Representing the Luminal Androgen Receptor Subtype of Triple Negative Breast Cancer.

The structures of four leucinostatin analogues (-) from spp. and spp. were determined together with six known leucinostatins [leucinostatins B (), A (), B2 (), A2 (), F (), and D ()].

Using the Cancer Dependency Map to Identify the Mechanism of Action of a Cytotoxic Alkenyl Derivative from the Fruit of .

An extract prepared from the fruit of exhibited differential cytotoxic effects when tested in a panel of pediatric cancer cell lines [Ewing sarcoma (A-673), rhabdomyosarcoma (SJCRH30), medulloblastoma (D283), and hepatoblastoma (Hep293TT)]. Bioassay-guided fractionation led to the purification of five new hydroquinone-based metabolites, choerosponols A-E (-), bearing unsaturated hydrocarbon chains. The structures of the natural products were determined using a combination of 1D and 2D NMR, HRESIMS, ECD spectroscopy, and Mosher ester analyses.

Elucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach.

The taccalonolide microtubule stabilizers covalently bind β-tubulin and overcome clinically relevant taxane resistance mechanisms. Evaluations of the target specificity and detailed drug-target interactions of taccalonolides, however, have been limited in part by their irreversible target engagement. In this study, we report the synthesis of fluorogenic taccalonolide probes that maintain the native biological properties of the potent taccalonolide, AJ.

Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products.

Covering: 2014-2019We review recent progress on natural products that target cytoskeletal components, including microtubules, actin, intermediate filaments, and septins and highlight their demonstrated and potential utility in the treatment of human disease. The anticancer efficacy of microtubule targeted agents identified from plants, microbes, and marine organisms is well documented. We highlight new microtubule targeted agents currently in clinical evaluations for the treatment of drug resistant cancers and the accumulating evidence that the anticancer efficacy of these agents is not solely due to their antimitotic effects.

Eribulin rapidly inhibits TGF-β-induced Snail expression and can induce Slug expression in a Smad4-dependent manner.

Background: Evidence shows that the anticancer effects of microtubule targeting agents are not due solely to their antimitotic activities but also their ability to impair microtubule-dependent oncogenic signalling.

Methods: The effects of microtubule targeting agents on regulators of TGF-β-induced epithelial-to-mesenchymal transition (EMT) were evaluated in breast cancer cell lines using high content imaging, gene and protein expression, siRNA-mediated knockdown and chromatin immunoprecipitation.

Results: Microtubule targeting agents rapidly and differentially alter the expression of Snail and Slug, key EMT-promoting transcription factors in breast cancer.

Correction: Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p130CAS/Src inhibition by eribulin.

[This corrects the article DOI: 10.18632/oncotarget.23798.

Fluorescence spectral shape analysis for nucleotide identification.

We report a conjugated polyelectrolyte fluorescence-based biosensor P-C-3 and a general methodology to evaluate spectral shape recognition to identify biomolecules using artificial intelligence. By using well-defined analytes, we demonstrate that the fluorescence spectral shape of P-C-3 is sensitive to minor structural changes and exhibits distinct signature patterns for different analytes. A method was also developed to select useful features to reduce computational complexity and prevent overfitting of the data.