Identification of a Novel Ferroptosis Inducer for Gastric Cancer Treatment Using Drug Repurposing Strategy.
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ABSTRACT:
SUBMITTER: Zhang J
PROVIDER: S-EPMC9289365 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Drug repurposing is also termed as drug repositioning or therapeutic switching. This method is applied to identify the novel therapeutic agents from the existing FDA approved clinically used drug molecules. It is considered as an efficient approach to develop drug candidates with new pharmacological activities or therapeutic properties. As the drug discovery is a costly, time-consuming, laborious, and highly risk process, the novel approach of drug repositioning is employed to increases the success rate of drug development. This strategy is more advantageous over traditional drug discovery process in terms of reducing duration of drug development, low-cost, highly efficient and minimum risk of failure. In addition to this, World health organization declared Coronavirus disease (COVID-19) as pandemic globally on February 11, 2020. Currently, there is an urgent need to develop suitable therapeutic agents for the prevention of the outbreak of COVID-19. So, various investigations were carried out to design novel drug molecules by utilizing different approaches of drug repurposing to identify drug substances for treatment of COVID-19, which can act as significant inhibitors against viral proteins. It has been reported that COVID-19 can infect human respiratory system by entering into the alveoli of lung via respiratory tract. So, the infection occurs due to specific interaction or binding of spike protein with angiotensin converting enzyme-2 (ACE-2) receptor. Hence, drug repurposing strategy is utilized to identify suitable drugs by virtual screening of drug libraries. This approach helps to determine the binding interaction of drug candidates with target protein of coronavirus by using computational tools such as molecular similarity and homology modeling etc. For predicting the drug-receptor interactions and binding affinity, molecular docking study and binding free energy calculations are also performed. The methodologies involved in drug repurposing can be categorized into three groups such as drug-oriented, target-oriented and disease or therapy-oriented depending on the information available related to quality and quantity of the physico-chemical, biological, pharmacological, toxicological and pharmacokinetic property of drug molecules. This review focuses on drug repurposing strategy applied for existing drugs including Remdesivir, Favipiravir, Ribavirin, Baraticinib, Tocilizumab, Chloroquine, Hydroxychloroquine, Prulifloxacin, Carfilzomib, Bictegravir, Nelfinavir, Tegobuvir and Glucocorticoids etc to determine their effectiveness toward the treatment of COVID-19.
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Project description:Notch signaling is a key parameter in regulating cell fate during tissue homeostasis, and an aberrant Notch pathway can result in mammary gland carcinoma and has been associated with poor breast cancer diagnosis. Although inhibiting Notch signaling would be advantageous in the treatment of breast cancer, the currently available Notch inhibitors have a variety of side effects and their clinical trials have been discontinued. Thus, in search of a more effective and safer Notch inhibitor, inhibiting recombinant signal binding protein for immunoglobin kappaJ region (RBPJ) specifically makes sense, as RBPJ forms a transcriptional complex that activates Notch signaling. From our established database of more than 10,527 compounds, a drug repurposing strategy-combined docking study and molecular dynamic simulation were used to identify novel RBPJ-specific inhibitors. The compounds with the best performance were examined using an in vitro cellular assay and an in vivo anticancer investigation. Finally, an FDA-approved antibiotic, fidaxomicin, was identified as a potential RBPJ inhibitor, and its ability to block RBPJ-dependent transcription and thereby inhibit breast cancer growth was experimentally verified. Our study demonstrated that fidaxomicin suppressed Notch signaling and may be repurposed for the treatment of breast cancer.
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Project description:Drug repurposing offers a promising alternative to dramatically shorten the process of traditional de novo development of a drug. These efforts leverage the fact that a single molecule can act on multiple targets and could be beneficial to indications where the additional targets are relevant. Hence, extensive research efforts have been directed toward developing drug based computational approaches. However, many drug based approaches are known to incur low successful rates, due to incomplete modeling of drug-target interactions. There are also many technical limitations to transform theoretical computational models into practical use. Drug based approaches may, thus, still face challenges for drug repurposing task. Upon this challenge, we developed a consensus inverse docking (CID) workflow, which has a ~ 10% enhancement in success rate compared with current best method. Besides, an easily accessible web server named auto in silico consensus inverse docking (ACID) was designed based on this workflow (http://chemyang.ccnu.edu.cn/ccb/server/ACID).
| S-EPMC6882193 | biostudies-literature
Project description:Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.
| S-EPMC8394389 | biostudies-literature
Project description:Chemotherapy is an effortless and frequently used approach in cancer therapy. However, in most cases, it can only prolong life expectancy and does not guarantee a complete cure. Furthermore, chemotherapy is associated with severe adverse effects, one of the major complications of effective cancer therapy. In addition, newly published research outputs show that cancer stem cells are involved in cancer disease progression, drug resistance, metastasis, and recurrence and that they are functional in the trans-differentiation capacity of cancer stem cells to cancer cells in response to treatments. Novel strategies are therefore required for better management of cancer therapy. The prime approach would be to synthesize and develop novel drugs that need extensive resources, time, and endurance to be brought into therapeutic use. The subsequent approach would be to screen the anti-cancer activity of available non-cancerous drugs. This concept of repurposing non-cancer drugs as an alternative to current cancer therapy has become popular in recent years because using existing anticancer drugs has several adverse effects. Micronutrients have also been investigated for cancer therapy due to their significant anti-cancer effects with negligible or no side effects and availability in food sources. In this paper, we discuss an ideal hypothesis for screening available non-cancerous drugs with anticancer activity, with a focus on cancer stem cells and their clinical application for cancer treatment. Further, drug repurposing and the combination of micronutrients that can target both cancers and cancer stem cells may result in a better therapeutic approach leading to maximum tumor growth control.
| S-EPMC10425757 | biostudies-literature
Project description:The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the significant role of the main protease of Covid-19 for virus replication, we performed a drug-repurposing study using the recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR, respectively, were developed using available small molecule inhibitors and utilized in the screening of the DrugBank repository. Further, a hierarchical docking protocol was implemented with the support of the Glide algorithm. The resultant compounds were then examined for their binding free energy against the main protease of Covid-19 by means of the Prime-MM/GBSA algorithm. Most importantly, the machine learning-based AutoQSAR algorithm was used to predict the antiviral activities of resultant compounds. The hit molecules were also examined for their drug-likeness and toxicity parameters through the QikProp algorithm. Finally, the hit compounds activity against the main protease was validated using molecular dynamics simulation studies. Overall, the present analysis yielded two potential inhibitors (DB02986 and DB08573) that are predicted to bind with the main protease of Covid-19 better than currently used drug molecules such as N3 (cocrystallized native ligand), lopinavir, and ritonavir.
| S-EPMC8250478 | biostudies-literature
Project description:Novel coronavirus first appeared in Wuhan, China, in December 2019, and it speedily expanded globally. Some medications which are used to treat other diseases seem to be effective in treating COVID-19 even without explicit support. The existing drugs that are summarized in this review primarily focused on therapeutic agents that possessed activity against other RNA viruses such as MERS-CoV and SARS-CoV. Drug repurposing or repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs such as corticosteroids, RNA-dependent RNA polymerase inhibitors, interferons, protease inhibitors, ivermectin, melatonin, teicoplanin, and some others. A search for new drug/drug targets is underway. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The possible impact of biologics for the management of COVID19 is promising and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and various types of vaccines. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. This article aims to review the roles of existing drugs and drug targets for COVID-19 treatment.
| S-EPMC8063850 | biostudies-literature
Project description:Motivation:Identification of novel therapeutic effects for existing US Food and Drug Administration (FDA)-approved drugs, drug repurposing, is an approach aimed to dramatically shorten the drug discovery process, which is costly, slow and risky. Several computational approaches use transcriptional data to find potential repurposing candidates. The main hypothesis of such approaches is that if gene expression signature of a particular drug is opposite to the gene expression signature of a disease, that drug may have a potential therapeutic effect on the disease. However, this may not be optimal since it fails to consider the different roles of genes and their dependencies at the system level. Results:We propose a systems biology approach to discover novel therapeutic roles for established drugs that addresses some of the issues in the current approaches. To do so, we use publicly available drug and disease data to build a drug-disease network by considering all interactions between drug targets and disease-related genes in the context of all known signaling pathways. This network is integrated with gene-expression measurements to identify drugs with new desired therapeutic effects based on a system-level analysis method. We compare the proposed approach with the drug repurposing approach proposed by Sirota et al. on four human diseases: idiopathic pulmonary fibrosis, non-small cell lung cancer, prostate cancer and breast cancer. We evaluate the proposed approach based on its ability to re-discover drugs that are already FDA-approved for a given disease. Availability and implementation:The R package DrugDiseaseNet is under review for publication in Bioconductor and is available at https://github.com/azampvd/DrugDiseaseNet. Supplementary information:Supplementary data are available at Bioinformatics online.
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Project description:The noninvasive nature of photodynamic therapy (PDT) enables the preservation of organ function in cancer patients. However, PDT is impeded by hypoxia in the tumor microenvironment (TME) caused by high intracellular oxygen (O2) consumption and distorted tumor blood vessels. Therefore, increasing oxygen generation in the TME would be a promising methodology for enhancing PDT. Herein, we proposed a concept of ferroptosis-promoted PDT based on the biochemical characteristics of cellular ferroptosis, which improved the PDT efficacy significantly by producing reactive oxygen species (ROS) and supplying O2 sustainably through the Fenton reaction. In contrast to traditional strategies that increase O2 based on decomposition of limited concentration of hydrogen peroxide (H2O2), our methodology could maintain the concentration of H2O2 and O2 through the Fenton reaction. Methods: For its association with sensitivity to ferroptosis, solute carrier family 7 member 11 (SLC7A11) expression was characterized by bioinformatics analysis and immunohistochemistry of oral tongue squamous cell carcinoma (OTSCC) specimens. Afterwards, the photosensitizer chlorin e6 (Ce6) and the ferroptosis inducer erastin were self-assembled into a novel supramolecular Ce6-erastin nanodrug through hydrogen bonding and π-π stacking. Then, the obtained Ce6-erastin was extensively characterized and its anti-tumor efficacy towards OTSCC was evaluated both in vitro and in vivo. Results: SLC7A11 expression is found to be upregulated in OTSCC, which is a potential target for ferroptosis-mediated OTSCC treatment. Ce6-erastin nanoparticles exhibited low cytotoxicity to normal tissues. More significantly, The over-accumulated intracellular ROS, increased O2 concentration and inhibited SLC7A11 expression lead to enhanced toxicity to CAL-27 cells and satisfactory antitumor effects to xenograft tumour mouse model upon irradiation. Conclusion: Our ferroptosis promoted PDT approach markedly enhances anticancer actions by relieving hypoxia and promoting ROS production, thereby our work provides a new approach for overcoming hypoxia-associated resistance of PDT in cancer treatment.
| S-EPMC6567978 | biostudies-literature
Project description:Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point.
| S-EPMC3872326 | biostudies-literature