Anticancer Chemotherapeutics Research Articles

Recent Advances in Strategies for Activation and Discovery/Characterization of Cryptic Biosynthetic Gene Clusters in Streptomyces.

Streptomyces spp. are prolific sources of valuable natural products (NPs) that are of great interest in pharmaceutical industries such as antibiotics, anticancer chemotherapeutics, immunosuppressants, etc. Approximately two-thirds of all known antibiotics are produced by actinomycetes, most predominantly by Streptomyces. Nevertheless, in recent years, the chances of the discovery of novel and bioactive compounds from Streptomyces have significantly declined. The major hindrance for obtaining such bioactive compounds from Streptomyces is that most of the compounds are not produced in significant titers, or the biosynthetic gene clusters (BGCs) are cryptic. The rapid development of genome sequencing has provided access to a tremendous number of NP-BGCs embedded in the microbial genomes. In addition, the studies of metabolomics provide a portfolio of entire metabolites produced from the strain of interest. Therefore, through the integrated approaches of different-omics techniques, the connection between gene expression and metabolism can be established. Hence, in this review we summarized recent advancements in strategies for activating cryptic BGCs in Streptomyces by utilizing diverse state-of-the-art techniques.

Methoxy-enriched cationic stilbenes as anticancer therapeutics.

Stilbene-based compounds are largely described for their antioxidant activity. But their use as anticancer chemotherapeutics is hampered by poor pharmacokinetic properties and non-selectivity towards cancer and non-cancer potency. To overcome these drawbacks, twin chain cationic lipid conjugated, methoxy-enriched stilbene derivatives were designed, synthesized and evaluated for their anticancer potency. Our findings reveal that HMSC16, a molecule with the highest number of methoxy groups and with C16-twin chain lipid, is the most potent as well as the most selective anticancer agent when compared to the other synthesized derivatives and commercially available stilbene-based drug, tamoxifen, and resveratrol. To justify these results, we have conducted a series of mechanistic experiments where we found that HMSC16 induced ROS generation, apoptosis, and autophagy by affecting the mitochondrial, lysosomal and nuclear pathways. Further cell cycle analysis data reveals that HMSC16 not only induces cell death but is also involved in the arrest of the cell cycle at the sub-G1 phase. Moreover, HMSC16 showed self-aggregation property owing to a possibly favorable hydrophilic-lipophilic balance. The self-aggregation property of HMSC16 allowed it to entrap hydrophobic drugs, withaferin. With entrapped withaferin, HMSC16 showed additive if not synergistic cell killing effect in HeLa cells. From the above results, we concluded that HMSC16 can be used not just as a drug but also as a drug delivery agent.

Antioxidant Properties and Redox-Modulating Activity of Chitosan and Its Derivatives: Biomaterials with Application in Cancer Therapy.

Many studies have shown that mitochondrial metabolism has a fundamental role in induction of carcinogenesis due to the influence of increased levels of reactive oxygen species (ROS) generation in all steps of oncogene transformation and cancer progression. It is widely accepted that the anticancer effect of conventional anticancer drugs is due to induction of oxidative stress and elevated intracellular levels of ROS, which alter the redox homeostasis of cancer cells. On the other hand, the harmful side effects of conventional anticancer chemotherapeutics are also due to increased production of ROS and disruption of redox homeostasis of normal cells and tissues. Therefore, there is a growing interest toward the development of natural antioxidant compounds from various sources, which could impact the redox state of cancer and normal cells by different pathways and could prevent damage from oxidant-mediated reactions. It is known that chitosan exhibits versatile biological properties, including biodegradability, biocompatibility, and a less toxic nature. Because of its antioxidant, antibacterial, anticancer, anti-inflammatory, and immunostimulatory activities, the biopolymer has been used in a wide variety of pharmaceutical, biomedical, food industry, health, and agricultural applications and has been classified as a new physiologically bioactive material.

Role of ATP-Binding Cassette Transporter Proteins in CNS Tumors: Resistance- Based Perspectives and Clinical Updates.

Despite gigantic advances in medical research and development, chemotherapeutic resistance remains a major challenge in complete remission of CNS tumors. The failure of complete eradication of CNS tumors has been correlated with the existence of several factors including overexpression of transporter proteins. To date, 49 ABC-transporter proteins (ABC-TPs) have been reported in humans, and the evidence of their strong association with chemotherapeutics' influx, dissemination, and efflux in CNS tumors, is growing. Research studies on CNS tumors are implicating ABC-TPs as diagnostic, prognostic and therapeutic biomarkers that may be utilised in preclinical and clinical studies. With the current advancements in cell biology, molecular analysis of genomic and transcriptomic interplay, and protein homology-based drug-transporters interaction, our research approaches are streamlining the roles of ABC-TPs in cancer and multidrug resistance. Potential inhibitors of ABC-TP for better clinical outcomes in CNS tumors have emerged. Elacridar has shown to enhance the chemo-sensitivity of Dasatanib and Imatinib in various glioma models. Tariquidar has improved the effectiveness of Temozolomide's in CNS tumors. Although these inhibitors have been effective in preclinical settings, their clinical outcomes have not been as significant in clinical trials. Thus, to have a better understanding of the molecular evaluations of ABC-TPs, as well as drug-interactions, further research is being pursued in research labs. Our lab aims to better comprehend the biological mechanisms involved in drug resistance and to explore novel strategies to increase the clinical effectiveness of anticancer chemotherapeutics, which will ultimately improve clinical outcomes.

Phytochemicals for the Prevention and Treatment of Gastric Cancer: Effects and Mechanisms.

Gastric cancer is the fifth most common cancer, and the third most prevalent cause of cancer-related deaths in the world. Voluminous evidence has demonstrated that phytochemicals play a critical role in the prevention and management of gastric cancer. Most epidemiological investigations indicate that the increased intake of phytochemicals could reduce the risk of gastric cancer. Experimental studies have elucidated the mechanisms of action, including inhibiting cancer cell proliferation, inducing apoptosis and autophagy, and suppressing angiogenesis as well as cancer cell metastasis. These mechanisms have also been related to the inhibition of Helicobacter pylori and the modulation of gut microbiota. In addition, the intake of phytochemicals could enhance the efficacy of anticancer chemotherapeutics. Moreover, clinical studies have illustrated that phytochemicals have the potential for the prevention and the management of gastric cancer in humans. To provide an updated understanding of relationships between phytochemicals and gastric cancer, this review summarizes the effects of phytochemicals on gastric cancer, highlighting the underlying mechanisms. This review could be helpful for guiding the public in preventing gastric cancer through phytochemicals, as well as in developing functional food and drugs for the prevention and treatment of gastric cancer.

Synthesis and cytotoxicity evaluation of novel cyclic/non-cyclic N-aryl enamino amides against human cancer cell lines.

Background and purpose:Considering the undesirable consequences of prevalent cancer diseases, design and development of potent and selective anticancer chemotherapeutics is a major concern. Several studies have unraveled the potential of dihydropyrimidinone (DHPM) scaffold toward generating anticancer agents.Experimental approach:In the present work, a series of new dihydropyrimidinethiones (DHPMTs) along with a few acyclic enamino amides were synthesized and evaluated for their cytotoxic activity against human gastric (AGS), liver (Hep-G2), and breast (MCF-7) cancer cell lines.Findings/Results:Among the assessed compounds, one of the DHPMT derivatives (compounds, one of the DHPMT derivatives (compound 5: 4-(3- fluorophenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-ttrahydropyrimidine-5-carboxamide) exhibited superior cytotoxicity in all of the target cell lines (AGS, IC50 9.9 μM; MCF-7, IC50 15.2 μM; and Hep-G2, IC50 40.5 μM). Cytotoxicity assessments showed that non-cyclic enamino amides exhibited weaker activities when compared to cyclic analogues (DHPMs).Conclusion and implications:DHPMTs were better cytotoxic agents than non-cyclic enamino amides. Structure activity relationship studies guided us toward the design of DHPMT derivatives with OH and NH groups particularly on meta position of 4-phenyl ring and hydrophobic bulky substituents on carboxamide side chain within the structure. Possible interaction with the hydrophobic site(s) of the cellular target was supposed. The results of this study emphasized the potential role of DHPMTs and their optimized derivatives as privileged medicinal scaffolds to inhibit the growth of gastric, breast, and liver cancer cells.

The N'-Substituted Derivatives of 5-Chloro-3-Methylisothiazole-4-Carboxylic Acid Hydrazide with Antiproliferative Activity.

Thanks to the progress in oncology, pharmacological treatment of cancer is gaining in importance and in the near future anti-cancer chemotherapeutics are expected to be the main method of treatment for cancer diseases. What is more, the search for new anti-cancer compounds with the desired application properties is constantly underway. As a result of designed syntheses, we obtained some new N’-substituted 5-chloro-3-methylisothiazole-4-carboxylic acid hydrazide derivatives with anticancer activity. The structure of new compounds was determined by mass spectrometry (MS), elemental analysis, proton nuclear magnetic resonance spectroscopy (1H-NMR), carbon nuclear magnetic resonance spectroscopy (13C-NMR), 1H-13C NMR correlations and infrared spectroscopy (IR). Moreover, the structures of the compounds were confirmed by crystallographic examination. The antiproliferative MTT tests for 11 prepared compounds was conducted towards human biphenotypic B cell myelomonocytic leukemia MV4-11. SRB test was used to examine their potential anticancer activity towards human colon adenocarcinoma cell lines sensitive LoVo, resistant to doxorubicin LoVo/DX, breast adenocarcinoma MCF-7 and normal non-tumorigenic epithelial cell line derived from mammary gland MCF-10A. The most active compound was 5-chloro-3-methyl-N′-[(1E,2E)-(3-phenyloprop-2-en-1-ylidene]isothiazole-4-carbohydrazide, which showed the highest antiproliferative activity against all tested cell lines.

Investigation on vitamin e succinate based intelligent hyaluronic acid micelles for overcoming drug resistance and enhancing anticancer efficacy

Multidrug resistance (MDR) is a major reason for anticancer chemotherapy failure, and P-glycoprotein (P-gp) over-expressing on tumor cells is considered as the important target to overcome MDR. Emerging reports have showed that vitamin E (VE) can cause significant reversal of MDR due to inhibition of ATPase activity. Accordingly, we synthesized hyaluronic acid (HA) conjugated vitamin E succinate (VES) polymer, which can self-assemble into micelles and thus achieve high drug (paclitaxel (PTX) used as model drug) encapsulation as well as tumor accumulation owing to the enhanced permeability and retention (EPR) effect and HA active targeting ability. In addition, the linker between HA and VES utilized in this work was disulfide bond with reduction-sensitive property, which would respond to high glutathione (GSH) concentration in tumor cytoplasmic environment and trigger HA-CYS-VES polymer disassociation and drug release. In vitro, PTX loaded HA-CYS-VES demonstrated enhanced cytotoxicity, high apoptosis-inducing activities and reversal effects of PTX on MCF-7/Adr cells, compared to PTX. Also, cellular uptake and intracellular PTX accumulation tests displayed that PTX loaded HA-CYS-VES could more efficiently enter tumor cells and selectively release drug in cytosol so as to facilitate its function on microtubule. More importantly, PTX loaded HA-CYS-VES showed better tumor targeting ability, improved antitumor efficacy and low adverse effects on tumor-bearing mice. In conclusion, PTX loaded HA-CYS-VES exhibited a great potential for reversing MDR in anticancer chemotherapeutics.

The first integrins β3-mediated cellular and nuclear targeting therapeutics for prostate cancer

Prostate cancer is one of the most commonly diagnosed cancers in men, leading to a high mortality rate due to a lack of effective anticancer treatment. Current anticancer chemotherapeutics are often administrated at suboptimal doses because of nonspecific toxicities to normal tissues, resulting in the eventual failure of therapy as well as the development of drug resistance and metastatic disease. Therefore, ligand-targeted therapeutics have the great potential of improving the selective anticancer toxicity. Integrins β3 (αvβ3 and αIIbβ3) are an important cell adhesion molecular family, overexpressed on both cell membrane and perinuclear region of prostate cancer cells, and play a key role in the progression and metastasis of prostate cancer, making them an attractive target for anticancer therapy. However, their clinical impacts have been limited due to lack of specific ligands. Here, for the first time, we have identified a peptide Arginine-Tryptophan-(D-Arginine)-Asparagine-Arginine as an integrins β3 specific ligand, named B3int, which shows superior selectivity to integrins β3 over other integrin subunits. B3int has high affinity to integrins β3 with a Kd value of 0.2 nM, which is 7-fold higher than c-RGDyK (1.4 nM), a well-established integrin αvβ3 ligand. In addition, B3int shows high specificity for integrins β3, and can selectively target integrin β3 overexpressed cancer cells in vitro and in vivo. Most importantly, B3int-modified liposomes (B3int-LS-DOX) can selectively deliver DOX not only into prostate cancer cells, but into nucleus via targeting integrins β3, thereby significantly improving anticancer effects in 2D prostate cancer cells and 3D tumor spheroids. Particularly, B3int-LS-DOX effectively inhibits tumor growth with an effective dose of as low as 1.5 mg/kg, which is 3.3-fold less than c-RGDyK-LS-DOX (5 mg/kg), indicating that integrins β3 specific therapy is a promising anticancer strategy which can greatly improve the anticancer therapeutic index. In summary, we have identified B3int as the first integrins β3 specific ligand with high affinity and specificity, and holds a great potential of improving the diagnosis and treatment for integrins β3-overexpressed cancers.

Quantitative determination of phagocytosis by bone marrow-derived dendritic cells via imaging flow cytometry.

Immunogenic cell death (ICD), induced by certain anticancer chemotherapeutics, leads to the emission of danger associated molecular patterns (DAMP) by cancer cells, which facilitates the attraction, activation and maturation of dendritic cells (DC) as well as the subsequent priming of effector T cells. In this context calreticulin (CALR) exposed at an early stage of ICD at the surface of the cancer cells serves as phagocytic signal and triggers the formation of immunological synapses between malignant cells and DC. Subsequent phagocytosis facilitates the transfer of tumor associated antigen and thus depicts a fundamental step in the generation of anticancer immunity. Here we provide an imaging flowcytometric protocol for the quantification of ICD-associated DC phagocytosis of cancer cells. As compared to the traditional flowcytometry-based analysis, the presented method offers additional means of differentiation between the transient formation of immunological synapses and the final DC-mediated phagocytosis of cancer cells.

Abstract 1232: Paclitaxel induces immunogenic cell death in ovarian cancer via TLR4-independent and dependent pathways

Abstract Immunogenic cell death refers to a phenomenon in which some of the cytotoxic chemotherapeutics kills the tumor cells and induces these dying cells to be immunogenic. The aim of this study is to investigate if the standard-of-care chemotherapy (carboplatin and paclitaxel) induces immunogenic cell death in ovarian cancer. We found that paclitaxel, but not carboplatin, induces multiple molecular determinants of immunogenic cell death (namely calreticulin exposure, ATP secretion, HMGB1 release, ANXA1 expression, and upregulation of CXCL10) in ID8 mouse ovarian cancer cells. By tumor vaccination assay in immunocompetent syngeneic mice, our results showed paclitaxel induces immunogenic cell death in the mice with ID8 ovarian tumor. Since toll-like receptor 4 (TLR4) is a receptor for paclitaxel, we generated isogenic derivatives of ID8 cells with Tlr4 knockout (KO) to investigate if paclitaxel induces immunogenic cell death is dependent on TLR4. Our results showed that the paclitaxel-induced molecular determinants of immunogenic cell death were diminished in the TLR4 KO clones when compared to wild-type controls. Moreover, the tumor vaccination assay showed that paclitaxel was not able to induce immunogenic cell death in mice with ovarian tumor with TLR4 KO. These results indicated that the paclitaxel requires TLR4 to induce immunogenic cell death. To explore the mechanisms of how paclitaxel induces immunogenic cell death through TLR4, we investigated the activation of PERK and phosphorylation of eIF2a in ER stress since they are the first two enumerate elements of the pathways that mediated calreticulin exposure in response to immunogenic anticancer chemotherapeutics. Our results, however, showed that paclitaxel induces activation of PERK and phosphorylation of eIF2a in ovarian cancer cells is independent on TLR4. We then investigate if paclitaxel induces SNARE-dependent exocytosis in mouse ovarian cancer cells because SNARE-dependent exocytosis is the final step of the pathways that mediated calreticulin exposure in immunogenic cell death. Our results showed that paclitaxel induces SNARE-dependent exocytosis of ATP-containing vesicles in mouse ovarian cancer cells via TLR4-mediated IKK2 activation. In summary, our results showed that paclitaxel induces immunogenic cell death in ovarian cancer through TLR4-independent and dependent pathways, in which paclitaxel-induced exocytosis is essential for the release of multiple molecular determinants of immunogenic cell death. Our results provide new evidence that the antitumor effect of paclitaxel occurs in part via activation of an immune response against cancer by inducing immunogenic cell death and provide a rationale for a new combination of paclitaxel and immunotherapies as an anticancer treatment. Citation Format: Tat-San Lau, Loucia Kit-Ying Chan, Gene Chi-Wai Man, Joseph Kwong. Paclitaxel induces immunogenic cell death in ovarian cancer via TLR4-independent and dependent pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1232.

Dual functionalized liposomes for efficient co-delivery of anti-cancer chemotherapeutics for the treatment of glioblastoma

Glioblastoma is a hostile brain tumor associated with high infiltration leading to poor prognosis. Anti-cancer chemotherapeutic agents have limited access into the brain due to the presence of the blood brain barrier (BBB). In this study, we designed a dual functionalized liposomal delivery system, surface modified with transferrin (Tf) for receptor mediated transcytosis and a cell penetrating peptide-penetratin (Pen) for enhanced cell penetration. We loaded doxorubicin and erlotinib into liposomes to enhance their translocation across the BBB to glioblastoma tumor. In vitro cytotoxicity and hemocompatibility studies demonstrated excellent biocompatibility for in vivo administration. Co-delivery of doxorubicin and erlotinib loaded Tf-Pen liposomes revealed significantly (p < 0.05) higher translocation (~15%) across the co-culture endothelial barrier resulting in regression of tumor in the in vitro brain tumor model. The biodistribution of Tf-Pen liposomes demonstrated ~12 and 3.3 fold increase in doxorubicin and erlotinib accumulation in mice brain, respectively compared to free drugs. In addition, Tf-Pen liposomes showed excellent antitumor efficacy by regressing ~90% of tumor in mice brain with significant increase in the median survival time (36 days) along with no toxicity. Thus, we believe that this study would have high impact for treating patients with glioblastoma.

Nanomaterial-Based Modulation of Tumor Microenvironments for Enhancing Chemo/Immunotherapy.

The tumor microenvironment (TME) has drawn considerable research attention as an alternative target for nanomedicine-based cancer therapy. Various nanomaterials that carry active substances have been designed to alter the features or composition of the TME and thereby improve the delivery and efficacy of anticancer chemotherapeutics. These alterations include disruption of the extracellular matrix and tumor vascular systems to promote perfusion or modulate hypoxia. Nanomaterials have also been used to modulate the immunological microenvironment of tumors. In this context, nanomaterials have been shown to alter populations of cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells. Despite considerable progress, nanomaterial-based TME modulation must overcome several limitations before this strategy can be translated to clinical trials, including issues related to limited tumor tissue penetration, tumor heterogeneity, and immune toxicity. In this review, we summarize recent progress and challenges of nanomaterials used to modulate the TME to enhance the efficacy of anticancer chemotherapy and immunotherapy.

QSAR and Anticancer Drug Design on Benzothienopyrimidinones as Promising Pim Kinase Inhibitors Utilizing Structural Descriptors

Pim kinase is a major target of anticancer chemotherapeutics. There are a number of pim kinase inhibitors which are being under clinical trials. But there are only a few QSAR and drug design attempts targeting pim kinase inhibition reported as of yet. Several 3H-Benzo[4,5]thieno[3,2-d]pyrimidin-4-one derivatives are taken into consideration here for the development of QSAR models utilizing topological and three dimensional structural indices against pim-1 and pim-2 kinase. Interesting results were found out where a model can produce an external prediction of 62.2% and 58.4% of variances for the inhibition of pim 1 and pim 2 kinases of the benzothienopyrimidinone compounds. Validated models have captured important structural features including electronegativity, polarizability and radial distribution function necessary for the inhibition of pim kinase. Such models have been utilized to screen a number of congeneric compounds from external ChMBL database. Further molecular docking was done to predict the mode of which may help to design new active congeners which are potent to inhibit pim kinase.

Macrophages as delivery vehicles for anticancer agents.

The delivery of anticancer agents via passive approaches such as the enhanced permeability and retention effect is unlikely to achieve sufficient concentrations throughout the tumor volume for effective treatment. Cell-based delivery approaches using tumor tropic cells have the potential to overcome the limitations of passive approaches. Specifically, this review focuses on the use of monocytes/macrophages for the delivery of a variety of anticancer agents, including nanoparticles, chemotherapeutics and gene constructs. The efficacy of this delivery approach, both as monotherapy and in combination with light-based phototherapy modalities, has been demonstrated in numerous in vitro and animal studies, however, its clinical potential remains to be determined.

Quantification of eIF2alpha phosphorylation during immunogenic cell death.

Immunogenic cell death (ICD) is a particular modality of cell death that can be triggered by selected anticancer chemotherapeutics. Tumor cells undergoing ICD can induce an adaptive anticancer immune response that targets residual cancer cells with the same antigenic profile. The activation of a full-blown immune response against the tumor antigen is preceded by the release or exposure of danger associated molecular patterns (DAMPs) by tumor cells that stimulate the attraction, activation and maturation of dendritic cells and eventually the antigen-specific priming of cytotoxic T lymphocytes (CTLs). The phosphorylation of the eukaryotic translation initiation factor (EIF2A) is a pathognomonic characteristic of ICD, which governs the release/exposure of DAMPs such as ATP and calreticulin and thus the immunogenicity of cell death. Here we describe techniques to detect eIF2alpha phosphorylation for the assessment of ICD.

Recent Developments of Supramolecular Metal-based Structures for Applications in Cancer Therapy and Imaging.

The biomedical application of discrete supramolecular metal-based structures, including supramolecular coordination complexes (SCCs), is still an emergent field of study. However, pioneering studies over the last 10 years demonstrated the potential of these supramolecular compounds as novel anticancer drugs, endowed with different mechanisms of action compared to classical small-molecules, often related to their peculiar molecular recognition properties. In addition, the robustness and modular composition of supramolecular metal-based structures allows for an incorporation of different functionalities in the same system to enable imaging in cells via different modalities, but also active tumor targeting and stimuli-responsiveness. Although most of the studies reported so far exploit these systems for therapy, supramolecular metal-based structures may also constitute ideal scaffolds to develop multimodal theranostic agents. Of note, the host-guest chemistry of 3D self-assembled supramolecular structures - within the metallacages family - can also be exploited to design novel drug delivery systems for anticancer chemotherapeutics. In this review, we aim at summarizing the pivotal concepts in this fascinating research area, starting with the main design principles and illustrating representative examples while providing a critical discussion of the state-of-the-art. A section is also included on supramolecular organometallic complexes (SOCs) whereby the (organic) linker is forming the organometallic bond to the metal node, whose biological applications are still to be explored. Certainly, the myriad of possible supramolecular metal-based structures and their almost limitless modularity and tunability suggests that the biomedical applications of such complex chemical entities will continue along this already promising path.

Biological evaluation of rare earth complexes bearing 1H‐imidazo[4,5‐f]‐1,10‐phenanthroline moiety as promising anticancer chemotherapeutics

Six lanthanide(III) complexes with the 2‐(naphthalen‐1‐yl)‐1H‐imidazo[4,5‐f]‐1,10‐phenanthroline ligand have been synthesized and characterized using X‐ray crystallography. The central Ln(III) center displays a distorted square antiprismatic environment with a N2O6 donor set. To study the reactivity of the complexes with possible biological targets, spectroscopic studies and viscosity experiments were used to research their interactions with calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA), taken as model biomolecules. The six complexes are moderate intercalating agents to CT‐DNA and can quench the intrinsic fluorescence of BSA in a static quenching process. Low IC50 values of these complexes were measured using MTT assays on three human cancer cell lines. One of the complexes could induce apoptosis of BEL‐7404 cancer cells via the extrinsic pathway with high expression of caspase‐8, resulting in caspase‐3 activation. Furthermore, that same complex could significantly suppress BEL‐7404 cell proliferation via induced apoptosis with G2/M phase cell cycle.

Small Molecule Inhibitors of HSF1-Activated Pathways as Potential Next-Generation Anticancer Therapeutics.

Targeted therapy is an emerging paradigm in the development of next-generation anticancer drugs. Heat shock factor 1 (HSF1) has been identified as a promising drug target because it regulates several pathways responsible for cancer cell growth, metastasis, and survival. Studies have clearly demonstrated that HSF1 is an effective drug target. Herein, we provide a concise yet comprehensive and integrated overview of progress in developing small molecule inhibitors of HSF1 as next-generation anticancer chemotherapeutics while critically evaluating their potential and challenges. We believe that this review will provide a better understanding of important concepts helpful for outlining the strategy to develop new chemotherapeutic agents with promising anticancer activities by targeting HSF1.

Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents

Antibody–drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.