Effective Anticancer Drugs Research Articles

Palladium catalysed cross coupling reactions on 2,3-isoxazol-17α-ethynyltestosterone, their anti-cancer activity, molecular docking studies and ADMET analysis

In the current study, the Sonogashira coupling reaction of danazol with aryl halides was carried out, yielding new aryl substituted danazol derivatives. The synthetic compounds were examined for anti-cancer potential on the HeLa human cervical cancer cell line, and they showed promising cytotoxic action. Synthesized compounds 2, 4 and 5 inhibited the growth of HeLa cervical cancer cells, potentially making them effective anti-cancer drugs in the future. Furthermore, molecular docking studies were performed to evaluate the inhibitory impact of danazol derivatives on the Human Papillomavirus (HPV) target protein (1F9F). The docking results showed a significant inhibitory action against the cervical cancer protein (1F9F). The binding energy (ΔG) values of 1, 2, 3, 4 and 5 against the protein 1F9F were −8.01, −8.70, −9.43, −9.58 and −9.75 kcal/mol, indicating a high affinity of the synthesized compounds to bind with the HPV target proteins compared to their parent compound danazol (1). ADMET analyses of all derivatives have also been carried out

Mebendazole effectively overcomes imatinib resistance by dual-targeting BCR/ABL oncoprotein and β-tubulin in chronic myeloid leukemia cells.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi-target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Carborane Conjugates with Ibuprofen, Fenoprofen and Flurbiprofen: Synthesis, Characterization, COX Inhibition Potential and In Vitro Activity.

The most effective anticancer drugs currently entail substantial and formidable side effects, and resistance of tumors to chemotherapeutic agents is a further challenge. Thus, the search for new anticancer drugs as well as novel therapeutic methods is still extremely important. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit COX (cyclooxygenase), overexpressed in some tumors. Carboranes are emerging as promising pharmacophores. We have therefore combined both moieties in a single molecule to design drugs with a dual mode of action and enhanced effectiveness. The NSAIDs ibuprofen, flurbiprofen, and fenoprofen were connected with 1,2-dicarba-closo-dodecaborane(12) via methylene, ethylene or propylene spacers. Three sets of carborane-NSAID conjugates were synthesized and analyzed through multinuclear (1H, 11B, and 13C) NMR spectroscopy. Conjugates with methylene spacers exhibited the most potent COX inhibition potential, particularly conjugates with flurbiprofen and fenoprofen, displaying higher selectivity towards COX-1. Furthermore, conjugates with methylene and ethylene spacers were more efficient in suppressing the growth of human cancer cell lines than their propylene counterparts. The carborane-flurbiprofen conjugate with an ethylene spacer was the most efficient and selective toward the COX-2-negative cell line HCT116. Its mode of action was basically cytostatic with minor contribution of apoptotic cell death and dominance of cells trapped in the division process.

Hybrid Molecules Containing Methotrexate, Vitamin D, and Platinum Derivatives: Synthesis, Characterization, In Vitro Cytotoxicity, In Silico ADME Docking, Molecular Docking and Dynamics.

Designing hybrid-based drugs is one promising strategy for developing effective anticancer drugs that explore combination therapy to enhance treatment efficacy, overcome the development of drug resistance, and lower treatment duration. Bisphosphonates and Vitamin D are commonly administered drugs for the treatment of bone diseases and the prevention of bone metastases. Platinum-based and methotrexate are widely used anticancer drugs in clinics. However, their use is hampered by adverse side effects. Hybrid-based compounds containing either bisphosphonate, vitamin D, platinum-based, or methotrexate were synthesized and characterized using FTIR, 1H-,31P, 13C-NMR, and UHPLC-HRMS which confirmed their successful synthesis. The hydroxyapatite bone binding assay revealed a promising percentage binding affinity of the bisphosphonate hybrid compounds. In vitro cytotoxicity assays on MCF-7 and HT-29 cell lines revealed a promising cytotoxic effect of hybrid 19 at 50 and 100 μg/mL on HT-29 and hybrid 15 on MCF-7 at 100 μg/mL. Molecular docking and dynamics simulation analysis revealed a binding affinity of -9.70 kcal/mol for hybrid 15 against Human 3 alpha-hydroxysteroid dehydrogenase type 3, showing its capability to inhibit Human 3 alpha-hydroxysteroid dehydrogenase type 3. The Swiss ADME, ProTox-II, GUSAR (General Unrestricted Structure-Activity Relationships), and molecular docking and dynamics studies revealed that these compounds are promising anticancer compounds.

New vatalanib analogs: Design, synthesis, in silico study and biological evaluation for anticancer activity

In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs. Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT‐116) using vatalanib as a positive control. The new candidates showed promising anticancer activity against two tested cancer cell lines with IC50 values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 µM, in particular compounds 11b and 11c which were more potent than vatalanib. The most potent was the 4-benzoylquinoxaline derivative 11b (IC50 = 6.04 ± 0.19 µM and 15.58 ± 0.58 µM) compared to vatalanib (IC50 of 25.27 ± 0.84 µM and 43.91 ± 1.64 µM) against HepG2 and HCT116, respectively. The selectivity indices of 11b were found to be approximately 14 and 5 towards HepG2 and HCT116, respectively. While vatalanib showed selectivity indices of about 5 and 3 towards HepG2 and HCT116, respectively. The most promising compound 11b was further investigated in HepG‐2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death. It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC50 of 0.918 ± 0.033 µM compared to vatalanib (IC50 of 0.265 ± 0.009 µM). Deep computational studies were created for the designed compounds including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates. The results of the docking study were consistent with biological testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib. So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead molecules for development of new effective anticancer drugs.

CaMKII Exacerbates Doxorubicin-Induced Cardiotoxicity by Promoting Ubiquitination Through USP10 Inhibition.

Doxorubicin (DOX) is an effective anticancer drug, but it has a problem of cardiotoxicity that cannot be ignored. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is tightly associated with the pathological progression of DOX-induced cardiotoxicity. Ubiquitin-specific protease 10 (USP10) plays an important role in many biological processes and cancers. However, its association with DOX-induced cardiotoxicity and CaMKII remains unclear. H9C2 cells, HL-1 cells and C57BL/6 mice were used to establish the DOX-induced cardiotoxicity model, and the CaMKII-specific inhibitor KN-93 and USP10 specific inhibitor Spautin-1 were used to observe the CaMKII and USP10 effect. In cell experiments, CCK-8 method was used to assess cell viability, LDH kit was used to assess lactate dehydrogenase expression, DCFH-DA staining was used to observe changes in active oxygen content, TUNEL staining was used to observe cell apoptosis, and Western blotting method was used to detect relevant protein markers. The expression of p-CaMKII and USP10 was assessed by immunofluorescence staining. In animal experiments, mouse echocardiograph was used were used to evaluate cardiac function, and HE staining and Masson staining were used to evaluate myocardial injury. Cardiomyocyte apoptosis was detected by TUNEL staining. Western blotting method was used to detect relevant protein markers. Our results demonstrated that activation of CaMKII and inhibition of USP10 pathway related to DOX-induced cardiotoxicity. Inhibition of CaMKII with KN-93 ameliorated DOX-induced cardiac dysfunction and cytotoxicity. In addition, CaMKII inhibition prevented DOX-induced apoptosis and ubiquitination. Furthermore, CaMKII inhibition increased USP10 expression in DOX-treated mouse hearts, H9C2 cells and HL-1 cells. At last, the USP10 inhibitor, Spautin-1, blocked the regulatory effect of CaMKII inhibition on apoptosis and ubiquitination in DOX-induced cardiotoxicity. Our findings revealed that DOX-induced myocardial apoptosis and activated CaMKII through cellular and animal levels, while providing a novel probe into the mechanism of CaMKII action: promoting ubiquitination by inhibiting USP10 aggravated apoptosis.

Molecular docking and ADME evaluation of plant-based bioactive molecules targeting nonsense-mediated mRNA decay pathway factors to modulate tumorigenesis

Cancer is a global health challenge that requires continuous efforts to discover effective anticancer drugs. Phytochemicals are compounds found in plants that often have medicinal properties. They possess a wide range of bioactive properties, including anticancer activity. Their multiple mechanisms of action in different physiological processes in humans make them promising candidates in the anticancer therapeutics development. The presence of these compounds makes plants valuable resources for traditional medicine and modern pharmaceutical research as well. Natural products from plants and marine sources are being used to find new anticancer agents. In humans, different cellular pathways are involved in the tumorigenesis process. Many studies have shown the role of the nonsense-mediated mRNA decay (NMD) pathway in the process of tumorigenesis. This NMD pathway is controlled by multiple proteins. In this study, we conducted a molecular docking analysis of 50 phytochemicals against the human NMD factor up-frameshit2 (UPF2) protein. The results of the molecular docking experiment and ADME properties indicate that 4 of these molecules (Genistein, Trihydroxyflavone, Baicalein and Epigallocatechin) have the potential to modulate the NMD pathway. Furthermore, these molecules comply with Lipinski's rule of five. The effects of these 4 phytochemicals may be further evaluated using in vitro and in vivo methods for novel anticancer therapeutic development.

Beyond ADCs: harnessing bispecific antibodies to directly induce apoptosis for targeted tumor eradication

Abstract Bispecific apoptosis triggers (BATs) are innovative bispecific antibodies designed to simultaneously target both a tumor-associated antigen and a cancer cell’s death receptor, thereby directly activating the extrinsic apoptotic pathway to induce death of cancer cells. This unique mechanism distinguishes BATs from antibody-drug conjugates (ADCs), which rely on cytotoxic drugs, and bispecific immune cell engagers such as bispecific T-cell engagers (BiTEs) and bispecific natural killer cell engagers (NKCEs), which recruit immune cells to eliminate target cancer cells. BATs offer significant potential advantages in clinical efficacy and safety over ADCs and BiTEs. Although the field is still emerging, recent advancements are highly promising, and analysis of preclinical and clinical data of DR5-targeting antibodies have been pivotal in outlining the criteria for the next generation of effective and safe medicines. Antibodies found inactive in preclinical testing were also found to be clinically ineffective, whereas antibodies with minimal preclinical results demonstrated moderate clinical activity. All clinical DR5-targeting antibodies were well tolerated by patients even at high doses (with the exception of TAS266 due to its unique design). These findings underscore the predictive value of robust preclinical models on clinical outcomes. Notably, first-in-class BAT, Cancerlysin™ IMV-M, demonstrated potent efficacy in diverse xenograft cancer models and safety in non-human primates, marking a significant advancement in developing safe and effective anti-cancer drugs.

Development of a novel N14-substituted antitumor evodiamine derivative with inhibiting heat shock protein 70 in non-small cell lung cancer

Notwithstanding the latest advancements in anticancer therapy, non-small cell lung cancer (NSCLC) remains a prominent contributor to cancer-associated mortality worldwide. Therefore, effective anti-cancer agents are required for the treatment of NSCLC. We previously demonstrated that the natural alkaloid evodiamine efficiently suppressed lung cancer cells and lung cancer stem-like cell populations by suppressing heat shock protein 70 (Hsp70). This finding inspired us to formulate evodiamine-based anti-cancer compounds against NSCLC. In this study, we synthesized a series of evodiamine derivatives with substitutions at the N14 position. EV206 was chosen for further study because it was the most effective among the 22 evodiamine derivatives at stopping H1299 cell growth. EV206 treatment efficiently suppressed cell viability and colony formation in both attached cells and in soft agar, even in those carrying drug resistance, by inducing apoptosis. The effectiveness of EV206 is approximately ten times greater than that of evodiamine. Normal cell viability was marginally affected by EV206 treatment. Additionally, EV206 efficiently decreased the cancer stem cell (CSC) population in the NSCLC cells. EV206 reduced the growth of H460 xenograft tumors without exhibiting toxic effects. These data implied that EV206 has the potential to be an effective Hsp70-targeting anticancer drug with low toxicity.

Adunctin E from Conamomum rubidum Induces Apoptosis in Lung Cancer via HSP90AA1 Modulation: A Network Pharmacology and In Vitro Study.

Lung cancer stands out as a leading cause of death among various cancer types, highlighting the urgent need for effective anticancer drugs and the discovery of new compounds with potent therapeutic properties. Natural sources, such as the Conamomum genus, offer various bioactive compounds. Adunctin E (AE), a dihydrochalcone derived from Conamomum rubidum, exhibited several pharmacological activities, and its potential as an anticancer agent remains largely unexplored. Thus, this study aimed to elucidate its apoptotic-inducing effect and identify its molecular targets. The network pharmacology analysis led to the identification of 71 potential targets of AE against lung cancer. Subsequent gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway enrichment analyses revealed the involvement of these targets in cancer-associated signaling pathways. Notably, HSP90AA1, MAPK1, and PIK3CA emerged as key players in apoptosis. In silico molecular docking and dynamic simulations suggested a strong and stable interaction between AE and HSP90AA1. In vitro experiments further confirmed a significant apoptotic-inducing effect of AE on lung cancer cell lines A549 and H460. Furthermore, immunoblot analysis exhibited a substantial decrease in HSP90AA1 levels in response to AE treatment. These findings support the potential anticancer activity of AE through the HSP90AA1 mechanism, underscoring its promise as a novel compound worthy of further research and development for anti-lung cancer therapy.

Susceptibility of HPV-18 Cancer Cells to HIV Protease Inhibitors.

Cervical cancer cases continue to rise despite all the advanced screening and preventative measures put in place, which include human papillomavirus (HPV) vaccination. These soaring numbers can be attributed to the lack of effective anticancer drugs against cervical cancer; thus, repurposing the human immunodeficiency virus protease inhibitors is an attractive innovation. Therefore, this work was aimed at evaluating the potential anticancer activities of HIV-PIs against cervical cancer cells. The MTT viability assay was used to evaluate the effect of HIV protease inhibitors on the viability of cervical cancer cells (HeLa) and non-cancerous cells (HEK-293). Further confirmation of the MTT assay was performed by confirming the IC50s of these HIV protease inhibitors on cervical cancer cells and non-cancerous cells using the Muse™ Count and Viability assay. To confirm the mode of death induced by HIV protease inhibitors in the HPV-associated cervical cancer cell line, apoptosis was performed using Annexin V assay. In addition, the Muse™ Cell Cycle assay was used to check whether the HIV protease inhibitors promote or halt cell cycle progression in cervical cancer cells. HIV protease inhibitors did not affect the viability of non-cancerous cells (HEK-293), but they decreased the viability of HeLa cervical cancer cells in a dose-dependent manner. HIV protease inhibitors induced apoptosis in HPV-related cervical cancer cells. Furthermore, they also induced cell cycle arrest, thus halting cell cycle progression. Therefore, the use of HIV drugs, particularly HIV-1 protease inhibitors, as potential cancer therapeutics represents a promising strategy. This is supported by our study demonstrating their anticancer properties, notably in HPV-associated cervical cancer cell line.

Application of Box-Behnken design in the optimization and development of albendazole-loaded zein nanoparticles as a drug repurposing approach for colorectal cancer management

Colorectal cancer (CRC) is the second cancer worldwide representing a major global health challenge. Numerous effective anticancer drugs have been developed in the last decade, yet the problem remains due to their low therapeutic index and nonspecificity. A new anticancer therapeutic paradigm is based on repurposing and nanoformulating drugs. Albendazole (ALB), a popular anthelmintic agent, was recently repurposed against CRC cells. In this study zein, an amphiphilic protein, was used to formulate nanoparticles (NPs) loaded with ALB. Box-Behnken design was selected to optimize the loaded NPs, the concentrations of polyvinyl alcohol, acetic acid, and the weight of zein were the independent variables. The dependent variables were the particle size, polydispersity index, and zeta potential. The optimized formula displayed a size of 84.3 ± 0.41 nm, PDI 0.13 ± 0.012, and a zeta potential of 42.5 ± 2.35 mV. ALB was successfully encapsulated into zein NPs and the release study revealed a desirable pH-responsive drug release behavior, that was negligible release during the first 2 h at pH 1.2 and progressive in the simulated colon environment reaching 71.1 ± 0.34 % at 6 h and 92.4 ± 1.11 % at 24 h. The anticancer effect of the loaded NPs on the human HCT116 cells showed favorable effects at 1 μM concentration with a significant decrease in the IC50 at days 2 and 3 upon loading albendazole into zein NPs. Zein nanoparticles proved to be prospective nanocarriers that could be used for the delivery of repurposed drugs in CRC treatment.

Anticancer Drug Discovery from Natural Compounds Targeting PI3K/AKT/mTOR Signaling Pathway.

The term cancer is used to describe a complex pathology characterized by the uncontrollable proliferation of cells, which displays a fast metastatic spread, being a disease with difficult treatment. In this context, Phosphatidylinositol 3-kinase (PI3K) represents a promising pathway to be inhibited, aiming to develop anticancer agents, since it performs a pivotal role in regulating essential cellular processes, including cell proliferation, growth, autophagy, and apoptosis. In parallel, natural compounds can effectively represent a therapeutic strategy to fight against malignant cells. Then, compounds derived from various plant sources, such as flavonoids, terpenoids, alkaloids, coumarins, and lignans, have exhibited remarkable in vitro and in vivo anticancer properties. This review focused in the exploration of natural products targeting the PI3K/AKT/m-TOR signaling pathway, demonstrating that these compounds could even further investigated to reveal novel and effective anticancer drugs in the future.

Advances in Anticancer Drug Discovery: Exploring the Untapped Potential of Natural Products for Targeted Therapies

Natural products have long been a significant source of structurally diverse and biologically active compounds, making them important for anticancer drug development. Taxol, a natural product isolated from the bark of the Pacific yew tree, is used to treat some cancers; Vincristine, a related compound that was eked out of the Madagascar periwinkle plant, treats leukemia and lymphoma. This review provides recent advances and future perspectives on developing natural-product-derived anticancer agents. We introduce celebrated examples of successfully developed natural-product-derived anticancer drugs, such as paclitaxel, doxorubicin, and camptothecin derivatives. We also discuss the hurdles of natural product-derived drug discovery, including limited availability, poor pharmacokinetics, and a lack of specificity to their intended targets. We will talk about some examples of these types of modification, including new developments in drug delivery systems, nanotechnology, and targeted drug delivery. These show how they could make natural product-derived anti-tumor drugs more effective and less harmful. It is emphasized that researchers from different fields, such as pharmacologists, catalyst chemists, drug delivery experts, rational drug designers, and nanotechnologists, will need to work together and research across disciplines for the project to succeed. This is so that problems and bottlenecks can be solved, and natural products can be used to make new anticancer drugs. Given the continuous and increasing global demand for novel anticancer drugs in the foreseeable future, natural products will remain a critically important source for discovering novel, safe, and effective anticancer drugs.

Widely-targeted in silico and in vitro evaluation of veratrum alkaloid analogs as FAK inhibitors and dual targeting of FAK and Hh/SMO pathways for cancer therapy: A critical analysis

Focal Adhesive Kinase (FAK), a key player in aggressive cancers, mediates signals crucial for progression, invasion, and metastasis. Despite advances in targeted therapies, drug resistance is still a challenge, and survival rates remain low, particularly for late-stage patients, emphasizing the need for innovative cancer therapeutics. Cyclopamine, a veratrum alkaloid, has shown promising anti-tumor properties, but the search for more potent analogs with enhanced affinity for the biological target continues.This study employs a hybrid virtual screening approach combining pharmacophore model-based virtual screening (PB-VS) and docking-based virtual screening (DB-VS) to identify potential inhibitors of the FAK catalytic domain. PB-VS on the PubChem database yielded a set of hits, which were then docked with the FAK catalytic domain in two stages (1st and 2nd DB-VS). Hits were ranked based on docking scores and interactions with the active site. The top three compounds underwent molecular dynamics simulations, alongside two control compounds (SMO inhibitor(s) and FAK inhibitor(s)), to assess stability through RMSD, RMSF, Rg, and SASA analyses. ADMET properties were evaluated, and compounds were filtered based on drug-likeness criteria.Molecular dynamics simulations demonstrated the stability of compounds when complexed with the FAK catalytic domain. Compounds 16 (−25 kcal/mol), 87 (−27.47 kcal/mol), and 88 (−18.94 kcal/mol) exhibited comparable docking scores, interaction profiles, stability, and binding energies, indicating their potential as lead candidates. However, further validation and optimization through quantitative structure-activity relationship (QSAR) studies are essential to refine their efficacy and therapeutic potential. The in vitro cell-based assay demonstrated that compound 101PF, a FAK inhibitor, significantly inhibited the proliferation and migration of A549 cells. However, the results regarding the combined effects of FAK and SMO inhibitors were inconclusive, highlighting the need for further investigation. This study contributes to developing more effective anti-cancer drugs by improving the understanding of potential cyclopamine-based veratrum alkaloid analogs with enhanced interactions with the FAK catalytic domain.

Novel quinolin-4-ylcarbonylhydrazine having N-(3-arylacryloyl) moiety: Design, synthesis and biological evaluation as potential cytotoxic agents against MDA-MB-231 via tubulin assembly inhibition

A new set of quinolin-4-ylcarbonylhydrazine derivatives 7a-i and 9a,b bearing 3-arylacryloyl moiety has been synthesized and investigated for their potential anticancer activity. The synthetic protocol involves the following step: the target quinoline derivatives 7a-i and 9a,b appended to the acryloyl moiety were synthesized from quinolin-4-carbohydrazide intermediate with respective ethyl 2-arylamido-3-arylacrylate compounds. The cytotoxic activity study was evaluated using the functional MTT method. The most of target compounds displayed potent cytotoxic activity against MDA-MB-231 cell line. Among them, compounds 7d and 7 h were found to be promising antiproliferative agents with IC50 values of 4.04 and 1.78 μM, respectively, relative to the effective anticancer drug, Dox (IC50 = 5.33 μM). Compound 7 h exhibited cytotoxic activity by causing cell cycle to block at G2/M phase in addition to pro-apoptotic effect, as shown by flow cytometric measurement. In addition, the inhibitory action against β-tubulin polymerization was investigated. Finally, compound 7 h diminished the level of mitochondrial potential by almost 2.8-fold compared to control, indicating that the cellular death proceeds through the provoke of the intrinsic mitochondrial pathway of apoptosis.

Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers.

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.

Recent Review on 1,3-Thiazole Derivatives as Therapeutic Targeted for Anticancer Activity

: In the past two decades, targeted cancer therapy has emerged as a novel class of anticancer therapeutics besides traditional chemotherapy, surgery, and radiotherapy. There is an extensive variety of anticancer drugs in the market, and several compounds are in various stages of clinical trials. Many studies indicate that these cytotoxic molecules are also associated with various types of toxicity and contrary side effects; thus, researchers all over the world are working to develop more effective and safer anticancer drugs. 1,3-thiazole derivatives have recently been identified as a novel class of cancer chemotherapeutic agents with promising activity against various tumors. In this review, we have systematically summarized and highlighted the latest developments in 1,3-thiazole derivative for anticancer activity.

Mitigating Doxorubicin-Induced Cardiotoxicity through Quercetin Intervention: An Experimental Study in Rats.

Doxorubicin (DOX) is an effective anticancer drug, but its use is limited by dose-dependent heart toxicity. Quercetin is a natural antioxidant frequently studied for its beneficial properties. Moreover, a wide range of dietary supplements are available for human use. This in vivo study aimed to explore the potential cardioprotective effects of quercetin in chronic DOX treatment. A total of 32 Wistar rats were randomly divided into four groups: control, DOX, DOX/Q-50, and DOX/Q-100, treated with saline, 2.5 mg/kg body-weight DOX, 2.5 mg/kg body-weight DOX + 50 mg quercetin, and 2.5 mg/kg body-weight DOX + 100 mg quercetin, respectively, for two weeks. Rats were monitored using cardiac ultrasound (US) and markers for cardiac injury. Oxidative damage and ultrastructural changes in the heart were investigated. Chronic DOX treatment led to a decline in cardiac function and elevated values of NT pro-BNP, troponin I, and CK-MB. Quercetin treatment slightly improved certain US parameters, and normalized serum NT pro-BNP levels. Furthermore, DOX-induced SOD1 depletion with consequent Nrf2 activation and DNA damage as shown by an increase in γH2AX and 8HOdG. Quercetin treatment alleviated these alterations. Oral administration of quercetin alleviated serum markers associated with DOX-induced cardiotoxicity. Furthermore, it exhibited a favorable impact on the cardiac US parameters. This suggests that quercetin may have potential cardioprotective properties.

DRN-CDR: A cancer drug response prediction model using multi-omics and drug features

Cancer drug response (CDR) prediction is an important area of research that aims to personalize cancer therapy, optimizing treatment plans for maximum effectiveness while minimizing potential negative effects. Despite the advancements in Deep learning techniques, the effective integration of multi-omics data for drug response prediction remains challenging. In this paper, a regression method using Deep ResNet for CDR (DRN-CDR) prediction is proposed. We aim to explore the potential of considering sole cancer genes in drug response prediction. Here the multi-omics data such as gene expressions, mutation data, and methylation data along with the molecular structural information of drugs were integrated to predict the IC50 values of drugs. Drug features are extracted by employing a Uniform Graph Convolution Network, while Cell line features are extracted using a combination of Convolutional Neural Network and Fully Connected Networks. These features are then concatenated and fed into a deep ResNet for the prediction of IC50 values between Drug – Cell line pairs. The proposed method yielded higher Pearson’s correlation coefficient (rp) of 0.7938 with lowest Root Mean Squared Error (RMSE) value of 0.92 when compared with similar methods of tCNNS, MOLI, DeepCDR, TGSA, NIHGCN, DeepTTA, GraTransDRP and TSGCNN. Further, when the model is extended to a classification problem to categorize drugs as sensitive or resistant, we achieved AUC and AUPR measures of 0.7623 and 0.7691, respectively. The drugs such as Tivozanib, SNX-2112, CGP-60474, PHA-665752, Foretinib etc., exhibited low median IC50 values and were found to be effective anti-cancer drugs. The case studies with different TCGA cancer types also revealed the effectiveness of SNX-2112, CGP-60474, Foretinib, Cisplatin, Vinblastine etc. This consistent pattern strongly suggests the effectiveness of the model in predicting CDR.