Anticancer Ability Research Articles

Fabrication of gemcitabine and losmapimod-prodrug loaded nanoparticles for the treatment and care of lung cancer

Lung carcinoma (LC) is rare cancer in most parts of the world but is common cancer in southern Asia. Local recurrent disease and distant metastasis of LC are still mysterious challenges. This investigation was to effectively fabricate and evaluate the therapeutic efficiency of Gemcitabine (GEM) and Losmapimod (LOS) encapsulated into polyethylene glycol (PEG)-polylactic-co-glycolic acid (PLGA)-NPs (GEM/LOS@NPs), which exhibited inhibition of in vitro lung cells proliferation. GEM/LOS@NPs with a diameter of ∼100 nm have been constructed employing an enhanced double-emulsion (W/O/W) method. The GEM/LOS@NPs’ particle size was studied through transmission electron microscopic (TEM) techniques and dynamic light scattering (DLS) measurement. After successfully fabricating GEM/LOS@NPs, the anticancer ability of A549 and H460 lung cancer cells was investigated. Biochemical assays such as AO/EB (acridine bromide/orange ethidium) and nuclear staining investigated the cancer cell’s morphology and death. The cell death of the cancer cells was synergically examined by ROS analysis. Overall, these results suggest that highly toxic drugs can be rationally transformed into self-deliverable and pharmacologically efficient monotherapy.

Activation of the β‑TrCP/IκBα/inflammation axis limits the sensitivity of liver cancer cells to neddylation inhibition.

Upregulation of protein neddylation occurs in numerous types of human cancer, including liver cancer. MLN4924, a potent neddylation-inhibiting pharmacological agent, demonstrates anticancer ability in numerous cancers. However, the sensitivity of MLN4924 in liver cancer remains unsatisfactory due to factors causing resistance. RT-qPCR and western blotting were utilized to assess the mRNA and protein levels of genes, respectively. Cell Counting Kit-8 assay and colony formation assays were employed to assess cell viability and proliferation. The pathway of protein degradation and stability were determined by western blotting after treatment with MG132 and cycloheximide. An immunoprecipitation assay was utilized to detect the ubiquitination of protein. An in vitro ubiquitination assay was used to determine the ubiquitin linkage. To the best of our knowledge, the present study was the first to demonstrate that NF-κB inhibitor α (IκBα) downregulation and subsequent inflammation in response to MLN4924 limited the antitumor potential of MLN4924. Ectopic expression of IκBα enhanced the antitumor potential of MLN4924 in liver cancer cells. Moreover, the results of the present study demonstrated that MLN4924 decreased IκBα via promoting the K48 linkage of ubiquitin to IκBα. Mechanistic studies demonstrated that MLN4924 enhanced the protein stability of β-transducin repeat-containing protein (β-TrCP), promoting the ubiquitination of IκBα, which led to the ubiquitin-mediated degradation of IκBα. In addition, the results of the present study also demonstrated that β-TrCP knockdown markedly inhibited MLN4924 from suppressing the growth of liver cancer cells, via attenuating MLN4924-mediated IκBα downregulation and inflammation. Collectively, these results indicated that the β-TrCP/IκBα/inflammation pathway may act as a novel resistance factor of MLN4924, and targeting β-TrCP may be beneficial for the treatment of liver cancer.

Pulsed electromagnetic therapy in cancer treatment: Progress and outlook

AbstractCancer is one of the major diseases that endanger human health. Current treatment options have low patient tolerance, poor prognosis, and strong side effects. Pulsed electromagnetic therapy can selectively kill cancer cells by taking advantage of their own electromagnetic sensitivity specificity. Pulsed electric fields (PEFs), pulsed electromagnetic fields (PEMFs), and cold atmospheric plasma (CAP) are three main means that have promising application in cancer therapy. Pulsed electromagnetic therapy showed significant anticancer ability in vitro and in vivo. In this paper, we summarize the basic principles, methods, and state of art research of PEFs, PEMFs, and PEMFs for cancer therapy. Based on cancer pro‐oxidation therapy, we propose a combination therapy of electromagnetic field‐enhanced CAP for cancer therapy.

Allyl Isothiocyanate (AITC) Induces Apoptotic Cell Death In Vitro and Exhibits Anti-Tumor Activity in a Human Glioblastoma GBM8401/luc2 Model.

Some clinically used anti-cancer drugs are obtained from natural products. Allyl isothiocyanate (AITC), a plant-derived compound abundant in cruciferous vegetables, has been shown to possess an anti-cancer ability in human cancer cell lines in vitro, including human brain glioma cells. However, the anti-cancer effects of AITC in human glioblastoma (GBM) cells in vivo have not yet been examined. In the present study, we used GBM8401/luc2 human glioblastoma cells and a GBM8401/luc2-cell-bearing animal model to identify the treatment efficacy of AITC. Here, we confirm that AITC reduced total cell viability and induced cell apoptosis in GBM8401/luc2 cells in vitro. Furthermore, Western blotting also showed that AITC induced apoptotic cell death through decreased the anti-apoptotic protein BCL-2, MCL-1 expression, increased the pro-apoptotic protein BAX expression, and promoted the activities of caspase-3, -8, and -9. Therefore, we further investigated the anti-tumor effects of AITC on human GBM8401/luc2 cell xenograft mice. The human glioblastoma GBM8401/luc2 cancer cells were subcutaneously injected into the right flank of BALB/c nude mice to generate glioblastoma xenograft mice. The animals were randomly divided into three groups: group I was treated without AITC (control); group II with 0.1 mg/day of AITC; and group III with 0.2 mg/day of AITC every 3 days for 27 days. Bodyweight, and tumor volume (size) were recorded every 3 days. Tumors exhibiting Luc2 intensity were measured, and we quantified intensity using Living Image software on days 0, 12, and 24. After treatment, tumor weight from each mouse was recorded. Tumor tissues were examined for histopathological changes using H&E staining, and we analyzed the protein levels via immunohistochemical analysis. Our results indicate that AITC significantly inhibited tumor growth at both doses of AITC due to the reduction in tumor size and weight. H&E histopathology analysis of heart, liver, spleen, and kidney samples revealed that AITC did not significantly induce toxicity. Body weight did not show significant changes in any experiment group. AITC significantly downregulated the protein expression levels of MCL-1, XIAP, MMP-9, and VEGF; however, it increased apoptosis-associated proteins, such as cleaved caspase-3, -8, and -9, in the tumor tissues compared with the control group. Based on these observations, AITC exhibits potent anti-cancer activity in the human glioblastoma cell xenograft model via inhibiting tumor cell proliferation and the induction of cell apoptosis. AITC may be a potential anti-GBM cancer drug that could be used in the future.

Properties and anticancer effects of plasma-activated medium stored at different temperatures

Plasma-activated solution (PAS) has attracted wide attention in cancer treatment because it can treat deep tumors and offer storability. The changes in reactive species and physicochemical properties of PAS during storage can affect its anticancer effect. In this study, the plasma-activated medium (PAM) was prepared by treating RPMI 1640 medium with afterglow gas generated by a custom-built air surface dielectric barrier discharge device. PAM was stored at four common temperature conditions (25 °C, 4 °C, −20 °C, and −80 °C) for 1 day, 4 days, and 7 days, and then, the physicochemical properties, reactive oxygen and nitrogen species (RONS), and the anti-cancer effect on A549 cells under different storage conditions were compared. The results showed that PAM exhibited different anticancer effects at different storage temperatures over a 7 day storage period. The anticancer ability of PAM under 80 °C storage remained stable after 7 days of storage and decreased at all other temperatures. These results were also verified by apoptosis results, and the differences were mainly related to the concentration of H2O2 and NO2−, and oxido reduction potential. Our results provided a theoretical basis for the storage of PAM and its application in anticancer therapy.

Self‐assembled nanoprodrugs from reducible dextran‐diethyldithiocarbamate conjugates for robust tumor‐targeted chemotherapy

AbstractThe development of anticancer prodrugs from repurposing approved drugs offers a rich source of potential new medicines for clinical cancer therapy. Herein, a folate‐decorated dextran prodrug (FADP) conjugate based on disulfiram (DSF), a repurposing drug, was designed for tumor‐targeted chemotherapy. The FADP conjugates with a high drug content (>10%) were readily achieved by the disulfide conjugation between orthopyridyl disulfide dextran (5, 10, and 20 kDa) and diethyldithiocarbamate (DDTC) as the metabolite of DSF. Data showed that the FADP conjugates could self‐assemble to form nanosized prodrugs (nanoprodrugs) with neutral surface charge under physiological conditions and that the nanoprodrugs could actively release DDTC in an intracellular reductive environment. In vitro experiments indicated that the FADP conjugates had a low cytotoxicity in CT‐26 cells but yielded marked cytotoxicity in the presence of copper (II) ions. Moreover, the FADP with 10 kDa of dextran (FADP10k) exerted the best anticancer ability in the cells with comparable anticancer efficacy to that of DSF. The significant anticancer ability of the FADP10k was associated with their folate receptor‐mediated uptake in the cells, following by a high cellular uptake level in comparison with the parent dextran prodrug (DP) without folates. The chemotherapy of the CT‐26 tumor xenografted in Balb/c mouse model elicited that the FADP10k group exerted marked tumor growth inhibition with a minor systemic toxicity at DDTC dose of 20 mg Kg−1 and the anticancer efficacy was superior to that obtained by the DP and DSF groups. This work highlights a high potential of DSF‐based dextran prodrugs for cancer chemotherapy.

Anticancer pH-Responsive Supramolecular Vesicles Fabricated Using Water-Soluble Pillar[5]arene and Curcumin Derivative

A pH-responsive curcuminoid delivery system based on supramolecular vesicles was fabricated via a novel host–guest inclusion complex between water-soluble pillar[5]arene (WP5) and hydrophobic bisdemethoxycurcumin (BDMC). This WP5 and BDMC (WP5 ⊃ BDMC) inclusion complex was studied using 1H NMR, UV–vis, and fluorescence spectroscopy. This resulting inclusion complex could self-assemble into well-defined supramolecular vesicles by host–guest interactions and presented a significant pH-responsive behavior, which was investigated using dynamic laser scattering, transmission electron microscopy, and UV–vis spectroscopy. The suitable preservation time for WP5 ⊃ BDMC and the construction ratio between host/guest molecules were both of great significance for the aggregated morphology of supramolecular vesicles. Furthermore, the BDMC complexes showed good anticancer ability in vitro, as they could inhibit HepG2 cell proliferation and migration. Therefore, the curcuminoid vesicles could provide a promising platform for drug delivery or food packaging utilization.

Prostate-specific membrane antigen targeted, glutathione-sensitive nanoparticles loaded with docetaxel and enzalutamide for the delivery to prostate cancer

Prostate cancer (PCa) is the most common malignant tumor in men. Chemotherapy with docetaxel (DTX) and novel hormonal agents such as enzalutamide (EZL) and abiraterone are the preferred first-line therapeutic regimens. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of PCa cells. This study aimed to prepare a PSMA targeted (Glutamate-Urea-Lysine, GUL ligand modified), glutathione (GSH)-sensitive (Cystamine, SS), DTX and EZL co-loaded nanoparticles (GUL-SS DTX/EZL-NPs) to treat PCa. Polyethylene glycol (PEG) was conjugated with oleic acid (OA) using a GSH-sensitive ligand: cystamine (PEG-SS-OA). GUL was covalently coupled to PEG-SS-OA to achieve GUL-PEG-SS-OA. GUL-PEG-SS-OA was used to prepare GUL-SS DTX/EZL-NPs. To evaluate the in vitro and in vivo efficiency of the system, human prostate cancer cell lines and PCa cells bearing mice were applied. Single drug-loaded nanoparticle and free drugs systems were utilized for the comparison of the anticancer ability. GUL-SS DTX/EZL-NPs showed a size of 143.7 ± 4.1 nm, with a PDI of 0.162 ± 0.037 and a zeta potential of +29.1 ± 2.4 mV. GUL-SS DTX/EZL-NPs showed high cancer cell uptake of about 70%, as well as higher cell growth inhibition efficiency (a maximum 79% of cells were inhibited after treatment) than single drug-loaded NPs and free drugs. GUL-SS DTX/EZL-NPs showed the most prominent tumor inhibition ability and less systemic toxicity. The novel GUL-SS DTX/EZL-NPs could be used as a promising system for PCa therapy.

Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents

A series of novel rhein-piperazine-dithiocarbamate hybrids 3 were efficiently synthesized from rhein through a catalyst-free and one-pot, three-step sequence involving chlorination and N-acylation followed by dithiocarbamate formation. Hybrids 3 were evaluated for their in vitro cytotoxic potency by MTT assay against several human cancer and non-cancer cells. Five of the hybrids were more cytotoxic to human lung cancer cell line A549 than the parent rhein and the reference, cytarabine (CAR). Structure-activity relationship (SAR) analysis indicated that cytotoxicity was significantly enhanced when ester groups were incorporated into the hybrids (3h–j). In particular, hybrid 3h (IC50 = 10.93 μg/mL), containing a long-chain alkyl ester, was the most potent compound toward A549 tumor cells, being 7- and 5-fold more toxic than rhein (IC50 = 77.11 μg/mL) and CAR (IC50 = 49.27 μg/mL), respectively. Additionally, hybrid 3h was less toxic to the corresponding normal human lung fibroblast cell line, WI-38, with a higher selectivity index (SI, WI-38/A549 ≈ 5) than doxorubicin (DOX, SI ≈ 0), CAR (SI ≈ 2) and rhein (SI ≈ 1). Furthermore, hybrid 3h displayed more toxicity against four types of lung cancer cells (A549, Calu-1, PC-9, and H460; IC50 = 10.81–23.78 μg/mL) than against six other types of cancer cells (Huh-7, 786-O, HCT116, Hela, SK-BR-3, and SK-OV-3; IC50 = 23.85–51.98 μg/mL). Further mechanistic studies showed that hybrid 3h induced apoptosis in a concentration-dependent manner in human lung adenocarcinoma cell line PC-9. In vivo safety studies showed that hybrid 3h had no acute toxicity to the major organs of mice and did not lead to blood biochemical index changes. Our results exhibit prominent anti-cancer cell inhibition ability and no obvious systemic toxicity to normal organs, indicating that hybrid 3h has promising potential for further applications in anti-lung cancer drug development.

Therapeutic application of carvacrol: A comprehensive review.

Carvacrol is a major natural constituent and is significantly present as an essential oil in aromatic plants and is well known for its numerous biological activities. Therapeutic properties of carvacrol have been demonstrated as anti-oxidant, anticancer, diabetes prevention, cardioprotective, anti-obesity, hepatoprotective and reproductive role, antiaging, antimicrobial, and immunomodulatory properties. The carvacrol biosynthesis has been mediated through mevalonate pathway. Carvacrol has the anticancer ability against malignant cells via decreasing the expressions of matrix metalloprotease 2 and 9, inducing apoptosis, enhancing the expression of pro-apoptotic proteins, disrupting mitochondrial membrane, suppressing extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signal transduction, and also decreasing the phosphoinositide 3-kinase/protein kinase B. It also decreased the concentrations of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase, and gamma-glutamyl transpeptidase as well as also restored liver function, insulin level, and plasma glucose level. Carvacrol also has been found to exert antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Coagulase-negative staphylococcus, Salmonella spp., Enterococcus sp. Shigella, and Escherichia coli. The current review article summarizes the health-promoting perspectives of carvacrol through various pathways.

Application value of a selenium-hydroxyapatite nanodelivery system as osteosarcoma treatment

To investigate the anticancer and osteogenic properties and mechanism of action of a selenium (Se4+) hydroxyapatite (HA) nanodelivery system for osteosarcoma (OS) therapy. We loaded different concentrations of Na2SeO3 (3% and 6%) into HA nanoparticles (HANP) for OS therapy. Simultaneously, we tested the stability and pH responsiveness of Se-HANP in vitro experiments, and OS MG-63 cells and mice BMSCs were cultured to further evaluate its permeability, anticancer ability and mineralization ability [alkaline phosphatase (ALP), osteocalcin (OCN)]. In addition, We conducted in vivo experiments by constructing OS mouse models to further investigate the anticancer mechanism of Se-HANP. Se-HANP showed good stability in blood; an acidic environment (pH 5) was more conducive to Se4+ ion release, and could effectively penetrate into OS MG-63 cells. In cell experiments, compared with HANP, Se-HANP could more effectively improve BMSCs viability and enhanced their mineralization performance, such as improving ALP and OCN levels. In addition, Se-HANP could effectively inhibit the activity and invasiveness of MG-63 cells; 6% Se-HANP showed stronger anticancer effects. In OS in vivo mouse experiments, Se-HANP could effectively inhibit tumor tissue growth (volume and weight) in a concentration dependent manner. In addition, Se4+ activated endogenous and exogenous apoptotic pathways by increasing the level of reactive oxygen species (8-OHdG) in tumor cells, leading to tumor cell apoptosis. Se-HANP could effectively penetrate OS cells, and its good stability and pH responsiveness could improve the anticancer efficiency of Se4+. Moreover, its excellent mineralization ability could effectively repair the bone defects caused by OS. Accordingly, Se-HANP can have great potential in OS treatment.

Coacervate-mediated novel pancreatic cancer drug Aleuria Aurantia lectin delivery for augmented anticancer therapy

BackgroundPancreatic cancer, one of the cancers with the highest mortality rate, has very limited clinical treatment. Cancer cells express abnormal glycans on the surface, and some lectins with a high affinity for the glycans induce apoptosis in cancer. In this study, the efficacy of Aleuria Aurantia lectin (AAL) for the treatment of pancreatic cancer was evaluated and the efficacy improvement through AAL delivery with mPEGylated coacervate (mPEG-Coa) was investigated.MethodsAAL was treated with pancreatic cancer cells, PANC-1, and the expression level of caspase-3 and subsequent apoptosis was analyzed. In particular, the anticancer efficacy of AAL was compared with that of concanavalin A, one of the representative anticancer lectins. Then, methoxypolyethylene glycol-poly(ethylene arginylaspartate diglyceride), a polycation, was synthesized, and an mPEG-Coa complex was prepared with polyanion heparin. The AAL was incorporated into the mPEG-Coa and the release kinetics of the AAL from the mPEG-Coa and the cargo protection capacity of the mPEG-Coa were evaluated. Finally, improved anticancer ability through Coa-mediated AAL delivery was assessed.ResultsThese results indicated that AAL is a potential effective pancreatic cancer treatment. Moreover, mPEG-Coa rapidly released AAL at pH 6.5, an acidic condition in the cancer microenvironment. The initial rapid release of AAL effectively suppressed pancreatic cancer cells, and the continuous supply of AAL through the Coa transporter effectively inhibited proliferation recurrence of cancer cells.ConclusionAAL is a potential novel drug for the treatment of pancreatic cancer therapeutic agent. In addition, a continuous supply of drugs above the therapeutic threshold using mPEG-Coa could improve therapeutic efficacy.

DNA intercalators as anticancer agents.

Cancer is one of the most prevailing disease conditions, which occurs due to uncontrolled cell division either due to natural mutation to the genes or due to changes induced by physical, chemical, or biological carcinogens. According to WHO, it is the second leading cause of death worldwide and has reported 10 million deaths in 2020. Hence, there arises the need for better chemotherapies and DNA intercalators are one such emerging therapy for cancer. DNA intercalating agents reversibly intercalate with the double-helical structure of DNA by interacting with adjacent base pairs and disrupting the structure of DNA and thereby causing cell death. Here, we discuss the different classes of organo-intercalators used in cancer therapy describing their anticancer and intercalation ability by different methods along with their structure-activity relationship and mechanism of action.

Present Status, Challenges, and Prospects of Dihydromyricetin in the Battle against Cancer.

Simple SummaryWith the advancements in diagnosis and treatment technology, the mortality of patients with cancer is gradually decreasing. However, further curbing cancer development requires searching for innovative and more effective drugs. Natural herbal medicine has apparent advantages in R&D and healthcare costs and is attracting increasing attention. Dihydromyricetin is a flavonoid compound with a promising anticancer effect extracted from the stems and leaves of Ampelopsis grossedentata. This paper reviews the different mechanisms of dihydromyricetin alone or in combination with other drugs against a variety of cancers to provide a comprehensive reference for the development of dihydromyricetin as an anticancer therapeutic agent.Dihydromyricetin (DHM) is a natural flavonoid compound extracted from Ampelopsis grossedentata that has been used for centuries in traditional Chinese medicine. DHM has attracted intensive attention due to its numerous beneficial activities, such as hepatoprotection, cardioprotection, antioxidant, and anti-inflammation. In addition, DHM inhibits the progression of cancers such as lung cancer, hepatocellular cancer, breast cancer, melanoma, and malignant reproductive systems through multiple mechanisms, including antiangiogenesis, antiproliferation, apoptosis, and inhibition of invasion and migration. Notably, DHM also activates autophagy at different levels, exerting a dual-regulatory effect on cancers. Mechanistically, DHM can effectively regulate mammalian target of rapamycin (mTOR), noncoding RNA-mediated signaling, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, nuclear factor-κB (NF-κB), p53, and endoplasmic reticulum stress (ER stress)-driven signaling in different types of cancers. DHM has also been shown to have inhibitory effects on various regulators that trigger epithelial–mesenchymal transition (EMT). Furthermore, DHM exhibits a remarkable anticancer reversal ability when used in combination with drugs such as adriamycin, nedaplatin, and other drugs. However, the low bioavailability of DHM limits its potential applications, which are improved through structural modification and the exploration of novel dosage forms. Therefore, DHM may become a promising candidate for treating malignancies alone or combined with conventional anticancer strategies used in clinical practice.

Combining radiation therapy with zoledronate for the treatment of osteo-invasive feline oral squamous cell carcinoma.

Feline oral squamous cell carcinoma (FOSCC) is the most common oral tumour diagnosed in pet cats and carries a poor prognosis with <10% one-year survival despite multi-modal therapies. Tumours of the mandible or maxilla are frequently osteo-invasive and pain can result from osteolysis. Zoledronate is a bisphosphonate that inhibits osteoclasts and reduces bone resorption. Radiation therapy (RT) is used to treat FOSCC due to anti-cancer activity and ability to improve quality of life. We hypothesized RT can be safely combined with zoledronate, and that this combinatory therapy would be efficacious, well tolerated, and result in decreased bone resorption in cats with FOSCC. SCCF1 cell line was treated with zoledronate before, concurrently, or after RT, and clonogenic assays were performed to determine if an optimal dosing schedule would be identified. Nine cats with osteoinvasive FOSCC were recruited for treatment with 4 weekly doses of 8Gy RT combined with zoledronate administered at the first and fourth treatments. Serial CT scans were performed to assess tumour response. Safety and tolerability were monitored with hematologic and biochemical parameters, and acute radiation effects were characterized. Serum c-telopeptide (CTx) and relative bone mineral density (rBMD) by dual -energy X-ray absorptiometry (DEXA) quantified bone resorption. In vitro studies showed no clear benefit to timing of zoledronate with RT, therefore all zoledronate was administered concurrently with RT in FOSCC patients. Based on tumour volume, 4/9 (44.4%) cats achieved partial remission, 4/9 (44.4%) stable disease and 1/9 (11.1%) had progressive disease. The combinatory therapy was well-tolerated based on biochemical measurements, and all patients experienced decreased serum CTx. Combining RT with zoledronate in tumour-bearing cats is safe, well-tolerated, results in a partial remission rate of up to 44%, and decreases serum CTx, a marker of bone resorption.

Molecular interaction of cryptophycin 52 with Caspase 8 for the management of lung cancer during coronavirus outbreak : A computational study.

It has been seen that, during COVID-19 outbreak lung cancer (LC) patients are noted as a high-risk population which make a more challenging to treatment of the LC patients. The active form of caspase-8 is involved in lung carcinogenesis in both humans and mice. In this study, the virtual screening was performed among 200 compounds retrieved from several resources for the searching of potent lead against Caspase 8 (Casp8). Cryptophycin 52 was found to have a strong inhibiting efficacy based on the free energy of binding with the active site of Casp8. The lowest binding energy was found to be -8.05 kcal/mole and was further analyzed for molecular dynamic simulation. Casp8 enzyme was determined to interact with cryptophycin 52 through twelve amino acid residues, specifically ARG260, SER316, GLY318, ASP319, THR337, VAL354, PHE355, PHE356, ILE357, GLN358, ALA359 and CYS360 along with six hydrogen bond particular, ILE357:N-UNK1: O7, UNK1: O14-PHE355:O, UNK1: C25-PHE355:O, UNK1: C35-THR337:O, UNK1: H65-HE355:O and UNK1: C25-PHE356. In addition, MD simulations for 50ns were performed for optimization, flexibility estimation and assessment of Casp8-cryptophycin 52 complex stability. This complex was seen as reasonably stable according to the RMSD, RMSF, and radius of gyration graph. Results obtained indicate cryptophycin 52 may be a lead compound with significant anti-cancer ability against Casp8. Further experimental work, however, is expected to support the compound's anti-cancer viewpoint.

Biosynthesis, Characterization, Anticancer activity and Drug delivery of Gold Nanoparticles synthesised from local isolate of Proteus mirabilis

Intracellular metal nanoparticles are produced by a variety of bacteria. As aqueous gold reacts with the Proteus mirabilis, it grows resulting in the formation of gold nanoparticles. The use of microorganisms in nanoparticle synthesis is gaining traction as an environmentally sustainable and exciting gold recovery process. This study consist of biological synthesis of gold nanoparticles utilizing the culture supernatant of local bacteria. Proteus mirabilis isolates when treated with HAuCl₄ solution in 10⁻³ Mm, then AuNPs were characterized and examined for anticancer ability using MTT assay against MCF-7 breast cancer cell lines. The size of the gold nanoparticles was rather consistent 29.18-55.57nm. Anticancer behavior studies revealed that gold nanoparticles had an equivalent strong anticancer impact. On the MCF-7 cell line, the AuNP concentration of 400 g/ml showed the greatest decrease. In addition, the combination of 400 g/ml AuNPs + 20 μM cisplatin resulted in the greatest reduction in the MCF-7 cell line.

Rational design of synthetically tractable HDAC6/HSP90 dual inhibitors to destroy immune-suppressive tumor microenvironment

IntroductionThe tumor microenvironment is mainly flooded with immunosuppressive cells and inhibitory cytokines, resulting in the inability of effective immune cells to infiltrate and recognize tumors and even the loss of anti-cancer ability. ObjectivesWe propose a novel HDAC6/HSP90 dual inhibitory strategy as well as a chemoimmunotherapeutic agent that does not only kill tumor cells but also destroys the tumor microenvironment and enhances anti-cancer immunity. MethodsA hybrid scaffold construction approach was leveraged to furnish a series of rationally designed resorcinol-based hydroxamates as dual selective HDAC6/HSP90 inhibitors. The drug design campaign commenced with a fragment recruitment process to pinpoint validated structural units to inhibit HDAC6 and HSP90, followed by their installation in flexible HDAC inhibitory templates via an efficient and facile multistep synthetic route. Subsequent evaluations identified a strikingly potent selective HDAC6/HSP90 dual inhibitor (compound 17) via molecular and biological analysis in vitro and in vivo. ResultsCompound 17 exhibited not only direct cytotoxicity to cancer cells but also downregulated immune checkpoints (PD-L1 and IDO) expression in tumors via the inhibition of STAT1 pathway and degradation of oncogene proteins (Src, AKT, Rb, and FAK), leading to in vivo tumor growth inhibition. These multiple effects enabled the effector T cells to largely infiltrate into the tumor region and release granzyme B to kill cancer cells. In addition, compound 17 also decreased TGF-β secretion from normal cells, resulting in the systemic reduction of immunosuppressive regulatory T cells. Delightfully, a cocktail treatment of compound 17 and anti-PD-1 antibodies demonstrated synergistic efficacy to eliminate solid tumors with 83.9% of tumor growth inhibition. ConclusionIn summary, the impressive activity profile of compound 17, as an effective anticancer agent and a potential immunosensitizer, forecasts the application of HDAC6/HSP90 dual inhibitory strategy to overcome the immunosuppressive tumor microenvironment.

Preparation, Characterization, and In Vitro Anticancer Activity Evaluation of Broccoli-Derived Extracellular Vesicle-Coated Astaxanthin Nanoparticles.

Astaxanthin (AST) is a type of ketone carotenoid having significant antioxidation and anticancer abilities. However, its application is limited due to its low stability and bioavailability. In our study, poly (lactic-co-glycolic acid) (PLGA)-encapsulated AST (AST@PLGA) nanoparticles were prepared by emulsion solvent evaporation method and then further processed by ultrasound with broccoli-derived extracellular vesicles (BEVs), thereby evolving as BEV-coated AST@PLGA nanoparticles (AST@PLGA@BEVs). The preparation process and methods were optimized by three factors and three levels of response surface method to increase drug loading (DL). After optimization, the DL was increased to 6.824%, and the size, polydispersity index, and zeta potential of AST@PLGA@BEVs reached 191.60 ± 2.23 nm, 0.166, and −15.85 ± 0.92 mV, respectively. Moreover, AST@PLGA@BEVs exhibited more notable anticancer activity than AST in vitro. Collectively, these results indicate that the method of loading AST in broccoli-derived EVs is feasible and has important significance for the further development and utilization of AST as a functional food.

Abstract 4003: Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death

Abstract For decades, chemotherapy has remained the standard of care for ovarian cancer patients. Although 70% of patients initially respond to platinum-based therapy, &amp;gt;90% succumb to chemoresistance. There is a need to uncover targeted drugs for ovarian cancer. A quicker, more cost-effective, and lower-risk route to identify new treatments is through repurposing FDA approved drugs. Using a computational drug repositioning platform, DrugPredict, we previously uncovered that the antiarrhythmic drug amiodarone potently decreases cell viability and triggers apoptosis in numerous patient-derived ovarian cancer cell lines through the degradation of c-Myc. However, given the dose-limiting toxicity of amiodarone, we applied structure-activity relationship to identify DL78, which lacks hERG activity but retains the anti-cancer properties and ability to regulate Myc. DL78 is significantly more potent and tumor specific than amiodarone. It rapidly induces G2/M arrest which ultimately leads to loss of Myc, mitotic catastrophe, and apoptosis in several types of cancer cells. Furthermore, pharmacokinetics studies show that the compound is retained in the tumor upon intraperitoneal injection and has reasonable solubility and permeability, yielding good absorption, distinct from amiodarone. Given its structural and molecular differences, we expect that DL78 works through a different mechanism that amiodarone and could represent an effective treatment for ovarian cancer and other MYC-driven tumors. Additional studies will establish the foundation for further development of this novel compound, as well as reveal targeted ovarian cancer vulnerabilities. Citation Format: Jessica McAnulty, Michele Dziubinski, Agharnan Gandhi, Margaret Farah, Pil Lee, Andrew D. White, Analisa DiFeo. Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4003.