Anticancer Discovery Research Articles

Machine learning for potential anti-cancer discovery from black sea cucumbers

<p>Despite being an abundant marine organism in Indonesia, black sea cucumbers <em>(Holothuria atra)</em> is still underutilised due to its slightly bitter taste. This study aims to identify potential anti-cancer compounds from black sea cucumbers using machine learning (ML) to perform drug discovery. ML models were used to predict interactions between compounds from the organism with cancer-related proteins. Following prediction, all compounds were computationally validated through molecular docking. The validated compounds were then screened using absorption, distribution, metabolism, excretion, and toxicity (ADMET) Lab 2.0 to assess their druglike properties. The results showed that ML predicted seven out of 86 compounds were interacted with cancer-related proteins. Computational validation from the results showed that four out of seven compounds demonstrated stable interaction with proteins where only one compound meet the criteria of drug-like compound. The framework of ML and computational validation highlighted in this study shows a great promise in the future of drug discovery specifically for marine organisms. Since computational method only works in prediction realms, wet lab validation and clinical trials are imperative before the drug candidate can be produced as actual anti-cancer drug.</p>

Anti-Cancer Activity of Synthesized 5-Benzyl juglone on Selected Human Cancer Cell Lines.

Cancer is a malignant disease that causes millions of deaths each year worldwide. As one of the cancer therapeutic strategies, chemotherapy is a means to destroy rapidly dividing cells. The main problem with cancer chemotherapy is the lack of selectivity of conventional chemotherapeutic drugs, leading to toxicity towards normal cells. Therefore, the discovery of anti-cancer agents with selectivity for fast-growing cancer cells is desirable. In this study, we report the synthesis and identification of synthesized 5-benzyl juglone as a potential anticancer agent with selectivity toward certain cancer cell lines. An efficient synthetic method for 5-benzyl juglone was established. The proliferation of cancer cell lines and a normal cell line treated by the target compound was studied using an MTT assay. In addition, the cell cycle arrest and apoptosis were determined by flow cytometry. Based on the Diels-Alder (D-A) reaction between 3,6-dimethoxy benzyne intermediate and furan, further acid-catalyzed intramolecular rearrangement, and CAN-mediated oxidation, a convenient synthesis of 5-benzyl juglone was achieved with high overall yield. The results from in vitro biological evaluation indicated that the juglone derivative exhibited potent antiproliferative activity against HCT-15 human colorectal cancer cells with an IC50 value of 12.27 μM. It exerted high inhibitory activity toward MCF-7 human breast cancer cells and, to a much lesser extent, to corresponding MCF-10A human breast epithelial normal cells with an IC50 ratio (IC50 in MCF-7 divided by IC50 in MCF-10A) of 0.62. The mechanistic investigations indicated that 5-benzyl juglone could induce cell cycle arrest at the G0/G1 phase and promote apoptosis of HCT-15 cells. The apoptotic effects possibly contributed to its higher selectivity toward cancer cells than normal cell lines.

Research hotspots and trends in discovery of anticancer agents from algae: A 20-year bibliometric and visualized analysis based on Web of Science and CiteSpace

In recent years, more and more metabolites with anticancer activity in algae have been isolated and identified, which are promising candidates for cancer therapy. In this work, a comprehensive bibliometric analysis was performed for better understanding the research hotspots and trends in discovery of anticancer agents from algae during 2003 to 2022. After retrieval from Web of Science core collection database, a total of 2804 most relevant publications were obtained, which were further systematically analyzed by using CiteSpace. Results showed that this field has attracted more attentions from researchers in the world, especially since 2019. China was the leading contributor to this field, but its collaborative partners were significantly less than that of USA, suggesting that Chinese researchers should conduct more cooperative studies with other investigators from other countries. Concerning the contributing journals, Algal Research was one of the top 10 productive journals in this field in terms of publication outcomes. Furthermore, current research hotspots and recently emerging sub-fields were discovered by using citation burst analysis, it showed that novel drug delivery systems, structure-activity relationships, and mechanisms of anticancer metabolites in vivo were the emerging topics in the future. This work would help policy makers, developers and researchers in discovery of anticancer agents from algae by providing them a bibliometric perspective on research hotspots and trends of this field, and spurring them to think about the field through various aspects.

Structure-Based Drug Design and Synthesis of Novel N-Aryl-2,4-bithiazole-2-amine CYP1B1-Selective Inhibitors in Overcoming Taxol Resistance in A549 Cells

As a promising therapeutic target for cancer, CYP1B1 is overexpressed in Taxol-resistant A549 cells; however, its role in drug resistance still remains unclear. Bioinformatic analysis data indicated that CYP1B1 was closely correlated with AKT/ERK1/2 and focal adhesion pathways, thereby playing an important role in Taxol resistance and cancer migration/invasion. Along similar lines, the AhR agonist 7,12-dimethylbenz[a]anthracene (DMBA) enhanced Taxol resistance and promoted migration/invasion of A549 and H460 cells likely stemming from CYP1B1 upregulation. Moreover, 83 novel N-aryl-2,4-bithiazole-2-amine CYP1B1-selective inhibitors were designed and synthesized to verify the role of CYP1B1 in Taxol-resistant A549 cells. Impressively, the most potent and selective one, namely, 77, remarkably inhibited AKT/ERK1/2 and FAK/SRC pathways and thereby reversed Taxol resistance as well as inhibited both migration and invasion of A549/Taxol cells. Collectively, this study not only displayed the role of CYP1B1 in Taxol resistance and cancer migration/invasion but also helped unlock the CYP1B1-oriented anticancer discovery.

Discovery of anticancer agents with c-Met inhibitory potential by virtual and experimental screening of a chemical library

c-Met receptor tyrosine kinase has recently emerged as an important target with therapeutic implications in pancreatic cancer. In this study, we carried out a docking virtual screening on an in-house library of 441 synthesized compounds and selected the compounds with the best interactions with the c-Met protein to be subjected to experimental tests. Ten compounds belonging to 3 different classes of chemical structures were selected for this purpose and their antiproliferative effects were studied against 4 pancreatic ductal adenocarcinoma (PDAC) cell lines including AsPC-1, Suit-2, Panc-1 and Mia-Paca-2 cells, primary PDAC cells and also c-Met amplified EBC-1 cell line by sulforhodamine-B assay. Apoptosis induction was examined by Hoechst 33258 staining and annexin V-FITC/propidium iodide flow cytometric assay. The best compound was also assayed in three-dimensional cultures of AsPC-1 cells and its c-Met inhibitory potential was studied by immunoblotting and a homogenous time resolved fluorescence (HTRF) assay. The compound with a phenanthrotriazine hydrazinyl scaffold bearing nitrophenyl pendant (PhTH) was the most active derivative, with IC50 values in the range of 5–8 μM. This compound exerted antiproliferative effect against AsPC-1 cells also in the presence of hepatocyte growth factor (HGF). PhTH induced apoptosis, dose-dependently inhibited spheroid growth, inhibited c-Met activity in cell-free HTRF assay and also inhibited the phosphorylation of c-Met and its downstream effector ERK1/2 in AsPC-1 cells. Molecular docking and dynamics simulation and MM-PBSA analysis confirmed close interactions of PhTH with c-Met kinase domain. Some of the tested compounds in this study seem to be potential c-Met inhibitors with promising activities against PDAC cells.

Natural products targeting human lactate dehydrogenases for cancer therapy: A mini review.

Reprogramming cancer metabolism has become the hallmark of cancer progression. As the key enzyme catalyzing the conversion of pyruvate to lactate in aerobic glycolysis of cancer cells, human lactate dehydrogenase (LDH) has been a promising target in the discovery of anticancer agents. Natural products are important sources of new drugs. Up to now, some natural compounds have been reported with the activity to target LDH. To give more information on the development of LDH inhibitors and application of natural products, herein, we reviewed the natural compounds with inhibition of LDH from diverse structures and discussed the future direction of the discovery of natural LDH inhibitors for cancer therapy.

Actinobacteria from Antarctica as a source for anticancer discovery

Although many advances have been achieved to treat aggressive tumours, cancer remains a leading cause of death and a public health problem worldwide. Among the main approaches for the discovery of new bioactive agents, the prospect of microbial secondary metabolites represents an effective source for the development of drug leads. In this study, we investigated the actinobacterial diversity associated with an endemic Antarctic species, Deschampsia antarctica, by integrated culture-dependent and culture-independent methods and acknowledged this niche as a reservoir of bioactive strains for the production of antitumour compounds. The 16S rRNA-based analysis showed the predominance of the Actinomycetales order, a well-known group of bioactive metabolite producers belonging to the Actinobacteria phylum. Cultivation techniques were applied, and 72 psychrotolerant Actinobacteria strains belonging to the genera Actinoplanes, Arthrobacter, Kribbella, Mycobacterium, Nocardia, Pilimelia, Pseudarthrobacter, Rhodococcus, Streptacidiphilus, Streptomyces and Tsukamurella were identified. The secondary metabolites were screened, and 17 isolates were identified as promising antitumour compound producers. However, the bio-guided assay showed a pronounced antiproliferative activity for the crude extracts of Streptomyces sp. CMAA 1527 and Streptomyces sp. CMAA 1653. The TGI and LC50 values revealed the potential of these natural products to control the proliferation of breast (MCF-7), glioblastoma (U251), lung/non-small (NCI-H460) and kidney (786-0) human cancer cell lines. Cinerubin B and actinomycin V were the predominant compounds identified in Streptomyces sp. CMAA 1527 and Streptomyces sp. CMAA 1653, respectively. Our results suggest that the rhizosphere of D. antarctica represents a prominent reservoir of bioactive actinobacteria strains and reveals it as an important environment for potential antitumour agents.

Harnessing Omics Approaches on Advanced Preclinical Models to Discovery Novel Therapeutic Targets for the Treatment of Metastatic Colorectal Cancer

Metastatic colorectal cancer (mCRC) remains challenging because of the emergence of resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapeutics, so more effective strategies to improve the patients’ outcome are needed. During the last decade, the application of a multi-omics approach has contributed to a deeper understanding of the complex molecular landscape of human CRC, identifying a plethora of drug targets for precision medicine. Target validation relies on the use of experimental models that would retain the molecular and clinical features of human colorectal cancer, thus mirroring the clinical characteristics of patients. In particular, organoids and patient-derived-xenografts (PDXs), as well as genetically engineered mouse models (GEMMs) and patient-derived orthotopic xenografts (PDOXs), should be considered for translational purposes. Overall, omics and advanced mouse models of cancer represent a portfolio of sophisticated biological tools that, if optimized for use in concert with accurate data analysis, could accelerate the anticancer discovery process and provide new weapons against cancer. In this review, we highlight success reached following the integration of omics and experimental models; moreover, results produced by our group in the field of mCRC are also presented.

TranScreen: Transfer Learning on Graph-Based Anti-Cancer Virtual Screening Model

Deep learning’s automatic feature extraction has proven its superior performance over traditional fingerprint-based features in the implementation of virtual screening models. However, these models face multiple challenges in the field of early drug discovery, such as over-training and generalization to unseen data, due to the inherently unbalanced and small datasets. In this work, the TranScreen pipeline is proposed, which utilizes transfer learning and a collection of weight initializations to overcome these challenges. An amount of 182 graph convolutional neural networks are trained on molecular source datasets and the learned knowledge is transferred to the target task for fine-tuning. The target task of p53-based bioactivity prediction, an important factor for anti-cancer discovery, is chosen to showcase the capability of the pipeline. Having trained a collection of source models, three different approaches are implemented to compare and rank them for a given task before fine-tuning. The results show improvement in performance of the model in multiple cases, with the best model increasing the area under receiver operating curve ROC-AUC from 0.75 to 0.91 and the recall from 0.25 to 1. This improvement is vital for practical virtual screening via lowering the false negatives and demonstrates the potential of transfer learning. The code and pre-trained models are made accessible online.

Discovery of Anticancer Agents from 2-Pyrazoline-Based Compounds.

As nitrogen-containing five-membered heterocyclic structural units, the substituted pyrazole derivatives have a broad spectrum of pharmacological activities, especially 4,5-dihydro-1H-pyrazoles that also commonly known as 2-pyrazolines. Since 2010, considerable studies have been found that the 2-pyrazoline derivatives possess potent anticancer activities. In the present review, it covers the pyrazoline derivatives reported by literature from 2010 till date (2010-2019). This review aims to establish the relationship between the anticancer activities variation and different substituents introduced into a 2-pyrazoline core, which could provide important pharmacophore clues for the discovery of new anticancer agents containing 2-pyrazoline scaffold.

CXCR4 signalling, metastasis and immunotherapy: zebrafish xenograft model as translational tool for anti-cancer discovery

Journal of Cancer Metastasis and Treatment is an open access journal, focusing on basic and clinical studies related to cancer cell, cell biology, oncology, radiation therapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neuro-oncology, etc.

Synthesis and evaluation of tetrahydroquinolin-2(1H)-one derivatives as novel anti-pancreatic cancer agents via targeting autophagy

Pancreatic cancer is one of the most deadly neoplasm with a 5-year survival rate of less than 6% owing to its remarkable tolerance to nutrient starvation, and new drugs and treatment strategies are urgently needed. During a project aiming at discovery of anticancer agents, we performed a structure modification on polycyclic polyprenylated acylphloroglucinols (PPAPs) skeleton, and discovered that PPAP rearranged to a tetrahydroquinolin-2(1H)-one feature. Here, series of tetrahydroquinolin-2(1H)-one derivatives were designed, synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (PANC-1), and the structure-activity relationship was also discussed. Among them, derivative 11k showed the most potent inhibitory activity with an IC50 value of 4.9 μM under nutrient-deprived condition. In contrast, all these derivatives exhibited low cytotoxicity against PANC-1 cells under normal nutrient condition, suggesting that the derivatives appeared to allow alternative tumor cell death mechanisms, and led to less toxicity. Further evaluations demonstrated that 11k decreased colony formation and induced the apoptosis of PANC-1 under nutrient-deprived condition in a concentration dependent manner. In in vivo study, 11k significantly suppressed the tumor development and weight in nude mice. Preliminary mechanism research revealed that 11k clearly downregulated LC3-II expression and increased the level of p62, two key autophagy markers and critical signals for pancreatic tumor growth and progression. Our current findings demonstrated that 11k might be a promising candidate for the new chemotherapeutic molecule of pancreatic cancer, and deserve further study.

Abstract 5541: Natural products as possible anti-cancer agents for digestive malignancies

Abstract Introduction: Natural products are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Historically, during the 1950s and 1960s anti-cancer agents for digestive malignancies, such as mitomycin and bleomycin, were isolated from actinobacteria; and then anti-cancer agents from plants, which include taxanes and camptothecin, were isolated. Their derivatives were also developed and are in clinical use. Purified ingredients and crude extracts from natural products such as PSK and those of Chinese herbal medicines are also in clinical use. Since the 1980s industries and academia have been focusing on strategies for development of targeted agents by screening a library of synthetic compounds; but recently natural products have been refocused on as a rich repository for drug discovery. Methods: To summarize the information of natural products as novel anti-cancer agents for digestive malignancies as well as their information in clinical trials, we surveyed literatures in the NCBI PudMed database and clinical trials registered in the FDA database, using keywords such as “natural products”, “anti-cancer agents”, and “digestive malignancy” or each of the malignancies (“esophageal cancer”, “stomach cancer”, “colorectal cancer”, “pancreatic cancer”, “biliary cancer” and others). We further classified the products on their chemical structures and their origins depending on types of drug-producing organisms. Results: With the above surveys, over 600 natural products were listed as possible substances as anti-cancer agents of digestive malignancies in preclinical development. Over 75% of the products were from plants. Their main structures consist of flavonoids, lignans, xanthones and others. The products from terrestrial animals and marine organisms were also listed. Curcumin, talaporfin sodium, eicosapentaenoic acid, resveratrol and other products are under clinical trials. Discussion: Despite many efforts, natural products have not been fully investigated for discovery of anti-cancer agents. New technologies having been applied for synthetic compounds, such as those for cultivation of drug-producing organisms, extraction and purification of substances, appreciation of targets, utilization of genomics information, and utilization of bioinformatics and cheminformatics with in silico analysis, can surely be utilized for anti-cancer drug discovery with natural products for digestive malignancies. Citation Format: Koh Miura, Masayuki Satoh, Makoto Kinouchi, Kuniharu Yamamoto, Yasuhiro Hasegawa, Yoichiro Kakugawa, Masaaki Kawai, Kiyoshi Uchimi, Hiroki Aizawa, Hiroto Sakurai, Tsuneaki Fujiya. Natural products as possible anti-cancer agents for digestive malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2015-5541

Anticancer Agents from Diverse Natural Sources

This review attempts to portray the discovery and development of anticancer agents/drugs from diverse natural sources. Natural molecules from these natural sources including plants, microbes and marine organisms have been the basis of treatment of human diseases since the ancient times. Compounds derived from nature have been important sources of new drugs and also serve as templates for synthetic modification. Many successful anti-cancer drugs currently in use are naturally derived or their analogues and many more are under clinical trials. This review aims to highlight the invaluable role that natural products have played, and continue to play, in the discovery of anticancer agents.

Advance in anti-cancer lead-compounds derived from natural products

Cancer is a serious threat to human life and health. Therefore, there is an emergent need to develop novel anti-cancer agents with new structural type, new mechanism of action and higher efficacy. Natural products had played a key role in the discovery of anticancer agents. The anti-cancer activity, mechanism of action, structure and activity relationship of several lead-compounds which were derived from natural products were summarized in this review.

Recent Progress in the Development of Histone Deacetylase Inhibitors as Anti-Cancer Agents

Histone deacetylases (HDACs) regulate the expression and activity of many proteins in both cancer initiation and cancer progression. HDACs are now recognized as promising targets for anticancer agent development. HDAC inhibitors (HDACIs) are emerging as promising anticancer drugs which possess tumor-selective cytotoxicity. HDACIs could promote growth arrest, differentiation, and apoptosis of cancer cells, with minimal effects on normal tissue. Research of HDACIs is now becoming an interesting field. HDACIs comprise structurally diverse anticancer agents and have been widely used in the clinic. This review describes recent progress in the development of HDACIs, especially focusing on the design strategies, novel chemical structures, biological properties and structure-activity relationships (SARs) of HDACIs. We hope it will be helpful for medicinal chemists who are interested in the discovery of anticancer agents.

Abelson Tyrosine-Protein Kinase 1 as Principal Target for Drug Discovery Against Leukemias. Role of the Current Computer-Aided Drug Design Methodologies

The discovery of anti-cancer agents is an area which continues in accelerated expansion. Leukemias (Lkms) are among the most investigated cancers due to its high and dominant prevalence in children. Computer-aided drug design (CADD) methodologies have been extremely important for the discovery of potent anti-Lkms agents, providing essential insights about the molecular patterns which could be involved in the appearance and development of anti-Lkms activity. The present review is focused on the role of the current CADD methodologies for the discovery of anti-Lkms agents with strong emphasis on the in silico prediction of inhibitors against the primary protein associated with the appearance of Lkms: Abelson tyrosine-protein kinase 1 (TPK-ABL1). In order to make a contribution to the field, we also developed a unified ligand-based approach by exploring Quantitative-Structure Activity Relationships (QSAR) studies. Here, we focused on the construction of two multi-targets (mt) QSAR models by employing a large and heterogeneous database of compounds. These models exhibited excellent statistical quality and predictive power to classifying more than 92% of inhibitors/ no inhibitors against seven proteins associated with Lkms, in both training and prediction sets. By using our unified ligand-based approach we identified several fragments as responsible for the anti-Lkms activity through inhibition of proteins, and new molecules were suggested as versatile inhibitors of the seven proteins under study.

Editorial [ Hot Topic :Recent Developments in the Discovery of Anticancer Agents (Guest Editors: Ahmed Kamal and Y.V.D.Nageswar)

Editorial [ Hot Topic :Recent Developments in the Discovery of Anticancer Agents (Guest Editors: Ahmed Kamal and Y.V.D.Nageswar)

Abstract 2537: Novel 2′-deoxycytidine analogs as DNA demethylation agents

Abstract Epigenetic therapies using cytidine/deoxycytidine analogs are proving to be effective as indicated by the recent approvals of 5-azacytidine (5-azaCyd) and 5-aza-2’-deoxycytidine (5-azadCyd) in myelodysplastic syndromes (MDS) and certain leukemias. Studies suggest that the inhibition of DNA cytosine-5 methylation and the re-expression of silenced tumor suppressors contribute to the beneficial effects of these drugs. However inhibition of DNA synthesis and other toxicities of these compounds represent major drawbacks in the clinic. Recently another analog previously examined in our anticancer discovery program, 4’-thio-2’-deoxycytidine (T-dCyd), had been shown to be an inhibitor of methyl transfer by the M. HhaI DNA cytosine-5 methyltransferase. In the current studies we demonstrate that T-dCyd and its 5-aza analogue 4’-thio-5-aza-2’-deoxycytidine (5-aza-T-dCyd), can deplete human DNMT1 protein in NCI-H23 lung carcinoma and the myeloid leukemia lines THP-1 and KG1a. Consistent with this we also found that T-dCyd and 5-aza-T-dCyd were also effective in decreasing DNMT activities in cancer cells. Methylation-specific PCR (MSP) analysis also demonstrated that both T-dCyd and 5-aza-T-dCyd induced CpG demethylation and re-expression of the tumor suppressor p15 in KG1a cells. We have also found that T-dCyd is inserted into replicating DNA at nanomolar doses as readily if not better than the natural 2’-deoxycytidine (dCyd) and exhibited very little toxicity at these doses. T-dCyd is therefore readily activated to its triphosphate T-dCTP, which is a good substrate for DNA polymerase mediated incorporation, and DNA polymerases also readily extend the chain after incorporation. Furthermore we also observed that T-dCyd and 5-aza-T-dCyd are efficacious in in vivo tumor models. Collectively our data suggest that these compounds or their analogs could be developed as novel DNA methylation inhibitors with better properties for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2537. doi:10.1158/1538-7445.AM2011-2537

New class of potent antitumor acylhydrazone derivatives containing furan

A pair of chemical isomeric structures of N-acylhydrazone compounds I and II were designed and synthesized. The reaction was carried out with high diastereoselectivity to obtain one configurational isomer in excellent yields. The exact configuration and conformation of IIa and IIe were confirmed by the X-ray single crystal diffraction. The antitumor bioassay revealed that some compounds exhibited excellent activity against the selected cancer cell lines. In particular, IIf (IC 50 = 16.4 μM) was better than doxorubicin (IC 50 = 53.3 μM) against human promyelocytic leukemic cells (HL-60). Their toxicities were predicted in silico. The results showed that compounds II were safe and eligible to be development candidates. IIf showed great promise as a novel lead compound for further anticancer discovery.