Antiproliferative Mechanism Research Articles

COVID-19 pandemic challenges: on the way to overcome obstacles in realization of PAH-specific therapy treatment goals

Our observation demonstrates a case of a 40-year-old female with idiopathic pulmonary arterial hypertension World Health Organization functional class III, who was admitted to NMRC of Cardiology repeatedly due to disease progression including dyspnea worsening and exercise tolerance decrease after previous COVID-19 infection on riociguat (7.5 mg daily), macitentan (10 mg daily) and selexipag (1600 mcg daily) therapy. Clinical examination demonstrated high-risk status according to the expected 1-year mortality. Due to unreleased treatment goals and high-risk status, we performed transition from selexipag to inhale iloprost. After therapy escalation the patient demonstrated a significant improvement in clinical condition, dyspnea reduction and exercise tolerance increase. The current treatment strategy for pulmonary arterial hypertension is based on regular multiparametric risk stratification approach in PAH patients. The impact of COVID-19 may become an important cause of clinical worsening in PAH patients during COVID-19 pandemic. Directed on vasodilatation and antiproliferation mechanisms of action of PAH-specific drugs are supposed to be protective in COVID-19 patients. However, the probability of clinical worsening in PAH patients despite PAH-specific therapy intake needs to be closely monitored to perform timely treatment correction in order to achieve low-risk status and to improve the prognosis of PAH patients.

Mechanistic Insights into the Selective Dual BET and PLK1 Inhibitory Activity of a Novel Benzamide Compound in Castration-Resistant Prostrate Cancer.

Though multifactorial, BET and PLK1 proteins have been found to be key players in the oncogenic process leading to castration-resistant prostate cancer through regulation of AR and MYC-mediated transcription. Hence, dual inhibition of these proteins appears to be an auspicious approach for CRPC therapy. WNY0824 has been reported to exhibit nanomolar range inhibition as well as significant anti-proliferative activity on AR-positive CRPC cells in vitro. However, structural, and mechanistic events associated with its dual inhibitory and anti-proliferative mechanisms remain unclear. Utilizing integrative computer-assisted atomistic techniques, analyses revealed that the dual-inhibitory activity of WNY0824 against BRD4 and PLK1 proteins is mediated by conserved residues present in the binding cavities of both proteins which are shown to elicit various strong intermolecular interactions and thus favour binding affinity. Also, binding orientation of the ligand at the protein binding cavities allowed for important hydrophobic interactions which resulted in high binding free energy of -42.50 kcal/mol and -51.64 kcal/mol towards BRD4 and PLK1, respectively. While van der Waals interactions are very important to ligand binding in BRD4-WNY complex, electrostatic interactions are pertinent to PLK1-WNY complex. Intriguingly, WNY0824 triggered conformational alterations in both proteins through increased structural instability, decreased structural compactness and mitigation in exposure of residues to solvent surface area. Consequently, critical interactions peculiar to the oncogenic activities of BRD4 and PLK1 were inhibited, a phenomenon that results in an antagonism of CRPC progression. The mechanistic insights presented in this report would further assist in the structure-based design of improved inhibitors useful in CRPC therapy.

Investigation of antiproliferative mechanisms of Alstonia angustiloba-silver nanoparticles in skin squamous cell carcinoma (A431 cell line)

Plant-based synthesis of silver nanoparticles (AgNPs) has emerged as a promising green synthesis method. Herein, we reported the biogenic synthesis of Alstonia angustiloba-AgNPs using the aqueous extract of A. angustiloba leaves and the assessment of its antiproliferative mechanisms. Initially, the physiochemical properties of A. angustiloba-AgNPs were characterised using UV–Vis spectrophotometry, FT-IR, FESEM, EDX, TEM, and zeta sizer analyses. The cytotoxicity of A. angustiloba aqueous extract and A. angustiloba-AgNPs was examined by MTT assays against the A431 cancer cell line. The morphology of the treated cells was examined using fluorescence microscopy and the antiproliferative mechanisms of the nanoparticles in A431 cells were investigated by annexin-FITC/propidium iodide (PI) staining and DNA cell cycle analysis using flow cytometry. The results revealed that the nanoparticles showed a spherical shape with a mean hydrodynamic size of 61.21 ± 3.96 nm and a zeta potential value of –18.67 ± 3.12 mV. The nanoparticles inhibited the growth of A431 cells with an IC50 value of 39.58 µg/mL after 72 h of treatment. Further investigation has shown that the nanoparticles induced both apoptosis and cell cycle arrest in A431 cells. In summary, the present study suggests that the biosynthesised A. angustiloba-AgNPs can be further exploited for potential anticancer applications.

Studies of Glyoxalase 1-Linked Multidrug Resistance Reveal Glycolysis-Derived Reactive Metabolite, Methylglyoxal, Is a Common Contributor in Cancer Chemotherapy Targeting the Spliceosome.

BackgroundTumor glycolysis is a target for cancer chemotherapy. Methylglyoxal (MG) is a reactive metabolite formed mainly as a by-product in anaerobic glycolysis, metabolized by glyoxalase 1 (Glo1) of the glyoxalase system. We investigated the role of MG and Glo1 in cancer chemotherapy related in multidrug resistance (MDR).MethodsHuman Glo1 was overexpressed in HEK293 cells and the effect on anticancer drug potency, drug-induced increase in MG and mechanism of cytotoxicity characterized. Drug-induced increased MG and the mechanisms driving it were investigated and the proteomic response to MG-induced cytotoxicity explored by high mass resolution proteomics of cytoplasmic and other subcellular protein extracts. Glo1 expression data of 1,040 human tumor cell lines and 7,489 tumors were examined for functional correlates and impact of cancer patient survival.ResultsOverexpression of Glo1 decreased cytotoxicity of antitumor drugs, impairing antiproliferative activity of alkylating agents, topoisomerase inhibitors, antitubulins, and antimetabolites. Antitumor drugs increased MG to cytotoxic levels which contributed to the cytotoxic, antiproliferative mechanism of action, consistent with Glo1-mediated MDR. This was linked to off-target effects of drugs on glycolysis and was potentiated in hypoxia. MG activated the intrinsic pathway of apoptosis, with decrease of mitochondrial and spliceosomal proteins. Spliceosomal proteins were targets of MG modification. Spliceosomal gene expression correlated positively with Glo1 in human tumor cell lines and tumors. In clinical chemotherapy of breast cancer, increased expression of Glo1 was associated with decreased patient survival, with hazard ratio (HR) = 1.82 (logrank p < 0.001, n = 683) where upper quartile survival of patients was decreased by 64% with high Glo1 expression.ConclusionsWe conclude that MG-mediated cytotoxicity contributes to the cancer chemotherapeutic response and targets the spliceosome. High expression of Glo1 contributes to multidrug resistance by shielding the spliceosome from MG modification and decreasing survival in the chemotherapy of breast cancer. Adjunct chemotherapy with Glo1 inhibitor may improve treatment outcomes.

Antiproliferative and Cytotoxic Efficacy of 10-Hydroxy-2-Decenoic Acid, Compared to Doxorubicin, on MCF-7 Breast Cancer Cells

Exploration of effective chemotherapy is needed for cancer treatment. 10-hydroxy-2-decenoic acid (10-H2DA), a unique fatty acid from royal jelly (RJ), is reported to have antitumor activities. However, its mechanisms remain under-examined. This study investigated the antiproliferative and cytotoxic efficacy of 10-H2DA treatments and their underlying mechanisms, compared to doxorubicin (DXR), on MCF-7 breast cancer cells. The antiproliferative effect was determined using the MTS tetrazolium assay. Cytotoxic activity was performed using a modified MTS assay. Cell cycle progression and cell apoptosis were analyzed by flow cytometry. Pivotal protein expressions were detected by Western blot. Results revealed that 125 µg/mL 10-H2DA treatment significantly inhibited cancer cell growth by 65 %, better than 0.54 µg/mL DXR treatment (48 %), compared to the medium control (p&lt;0.05). The 50 % lethal concentration (LC50) values of 10-H2DA were 190 µg/mL, representing cytotoxic activity. The underlying antiproliferative and cytotoxic mechanisms of 125 µg/mL 10-H2DA treatment demonstrated that it extensively suppressed c-MYC/BAX and slightly activated p53/BAX, leading to G0/G1 cell cycle arrest (decreased cyclin D1 and CDK4) and cell apoptosis (decreased BCL2/BAX). It slightly limited lifespan extension (decreased hTERT/BAX). Nevertheless, it strongly activated HO-1/BAX and NRF2/BAX, possibly inducing chemoresistance and cell invasion later on. Our findings suggested that 10-H2DA treatments induced antiproliferative effects on MCF-7 breast cancer cells via suppression of c-MYC, CDK4, and cyclin D1, leading to cell cycle arrest and cell apoptosis. However, long-term treatment may increase chemoresistance and cell invasion due to induction of antioxidative power, NRF2/BAX, and HO-1/BAX. Therefore, aggressive treatment for a short period would be recommended for using 10-H2DA as a chemotherapeutic compound to prevent chemoresistance and cell invasion. Further long-term in vitro and in vivo studies are necessary to confirm its strength and weakness.&#x0D; HIGHLIGHTS&#x0D; &#x0D; 10-hydroxy-2-decenoic acid (10-H2DA), a marker royal jelly acid, effectively inhibited MCF-7 breast cancer cells proliferation and induced cytotoxicity&#x0D; The inhibitory mechanisms involved the high suppression of c-MYC, cyclin D1, and CDK4, which induced cell cycle arrest and cell apoptosis&#x0D; 10-H2DA treatment at proper dose induced high antioxidative potency via activation of NRF2/BAX and HO-1/BAX&#x0D; Limitation of 10-H2DA treatment is that it might induce chemoresistance&#x0D; &#x0D; GRAPHICAL ABSTRACT

Effect of Resveratrol Treatment on Human Pancreatic Cancer Cells through Alterations of Bcl-2 Family Members.

Pancreatic cancers are among of the most lethal types of neoplasms, and are mostly detected at an advanced stage. Conventional treatment methods such as chemotherapy or radiotherapy often do not bring the desired therapeutic effects. For this reason, natural compounds are increasingly being used as adjuvants in cancer therapy. Polyphenolic compounds, including resveratrol, are of particular interest. The aim of this study is to analyze the antiproliferative and pro-apoptotic mechanisms of resveratrol on human pancreatic cells. The study was carried out on three human pancreatic cancer cell lines: EPP85-181P, EPP85-181RNOV (mitoxantrone-resistant cells) and AsPC-1, as well as the normal pancreatic cell line H6c7. The cytotoxicity of resveratrol in the tested cell lines was assessed by the colorimetric method (MTT) and the flow cytometry method. Three selected concentrations of the compound (25, 50 and 100 µM) were tested in the experiments during a 48-h incubation. TUNEL and Comet assays, flow cytometry, immunocytochemistry, confocal microscopy, real-time PCR and Western Blot analyses were used to evaluate the pleiotropic effect of resveratrol. The results indicate that resveratrol is likely to be anticarcinogenic by inhibiting human pancreatic cancer cell proliferation. In addition, it affects the levels of Bcl-2 pro- and anti-apoptotic proteins. However, it should be emphasized that the activity of resveratrol was specific for each of the tested cell lines, and the most statistically significant changes were observed in the mitoxantrone-resistant cells.

3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis.

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18–1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4′,6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.

Antioxidant and antiproliferative potential of ethanolic extracts from Moringa oleifera, Tropaeolum tuberosum and Annona cherimola in colorrectal cancer cells

Moringa oleifera, Tropaeolum tuberosum and Annona cherimola are medicinal plants traditionally used in Ecuador. However, their therapeutic properties are not completely known. We analyzed chromatographically ethanolic extracts of the seeds of M. oleifera, A. cherimola and the tubers of T. tuberosum; all presented a high content of polyphenols. The extract of A. cherimola showed the highest antioxidant activity and M. oleifera had the highest capacity to enhance the activity of detoxifying enzymes such as glutathione S-transferase and quinone oxidoreductase. The antitumor effect of these extracts was evaluated in vitro with colorectal cancer (CRC) cell lines T84, HCT-15, SW480 and HT-29, as well as with cancer stem cells (CSCs). A. cherimola and M. oleifera extracts presented the lowest IC50 in T-84 and HCT-15 (resistant) cells, respectively, as well as the highest level of inhibition of proliferation in multicellular tumor spheroids of HCT-15 cells. The inhibitory effect on CSCs is noteworthy because in vivo, these cells are often responsible for cancer recurrences and resistance to chemotherapy. Moreover, all extracts showed a synergistic activity with 5-Fu. The antiproliferative mechanism of the extracts was related to overexpression of caspases 9, 8 and 3 and increased production of reactive oxygen species. In addition, we observed cell death by autophagy in M. oleifera and T. tuberosum extracts. Therefore, these ethanolic extracts are excellent candidates for future molecular analysis of the presence of bioactive compounds and in vivo studies which could improve colon cancer therapy.

Soft Coral-Derived Dihydrosinularin Exhibits Antiproliferative Effects Associated with Apoptosis and DNA Damage in Oral Cancer Cells.

Dihydrosinularin (DHS) is an analog of soft coral-derived sinularin; however, the anticancer effects and mechanisms of DHS have seldom been reported. This investigation examined the antiproliferation ability and mechanisms of DHS on oral cancer cells. In a cell viability assay, DHS showed growth inhibition against several types of oral cancer cell lines (Ca9-22, SCC-9, OECM-1, CAL 27, OC-2, and HSC-3) with no cytotoxic side effects on non-malignant oral cells (HGF-1). Ca9-22 and SCC-9 cell lines showing high susceptibility to DHS were selected to explore the antiproliferation mechanisms of DHS. DHS also causes apoptosis as detected by annexin V, pancaspase, and caspase 3 activation. DHS induces oxidative stress, leading to the generation of reactive oxygen species (ROS)/mitochondrial superoxide (MitoSOX) and mitochondrial membrane potential (MitoMP) depletion. DHS also induced DNA damage by probing γH2AX phosphorylation. Pretreatment with the ROS scavenger N-acetylcysteine (NAC) can partly counter these DHS-induced changes. We report that the marine natural product DHS can inhibit the cell growth of oral cancer cells. Exploring the mechanisms of this cancer cell growth inhibition, we demonstrate the prominent role DHS plays in oxidative stress.

Potential Health Benefits of Curcumin on Female Reproductive Disorders: A Review.

Curcumin is one of the main polyphenolic compounds in the turmeric rhizome. It possesses antioxidant, anti-inflammatory, anti-cancer, anti-arthritis, anti-asthmatic, anti-microbial, anti-viral and anti-fungal properties. This review aims to provide an overview of the potential health benefits of curcumin to treat female reproductive disorders, including polycystic ovary syndrome (PCOS), ovarian failure and endometriosis. Comprehensive information on curcumin was retrieved from electronic databases, which were MEDLINE via EBSCOhost, Scopus and Google Scholar. The available evidence showed that curcumin reduced the high level of androgen in PCOS. Studies in rodents suggest that curcumin resulted in the disappearance of cysts and the appearance of healthy follicles and corpora lutea. Furthermore, animal studies showed curcumin improved the overall function of the ovary in ovarian diseases and reversed the disturbance in oxidative stress parameters. Meanwhile, in vitro and in vivo studies reported the positive effects of curcumin in alleviating endometriosis through anti-inflammatory, anti-proliferative, anti-angiogenic and pro-apoptotic mechanisms. Thus, curcumin possesses various effects on PCOS, ovarian diseases and endometriosis. Some studies found considerable therapeutic effects, whereas others found no effect. However, none of the investigations found curcumin to be harmful. Curcumin clinical trials in endometriosis and ovarian illness are still scarce; thus, future studies need to be conducted to confirm the safety and efficacy of curcumin before it could be offered as a complementary therapy agent.

Nepenthes Ethyl Acetate Extract Provides Oxidative Stress-Dependent Anti-Leukemia Effects

Several kinds of solvents have been applied to Nepenthes extractions exhibiting antioxidant and anticancer effects. However, they were rarely investigated for Nepenthes ethyl acetate extract (EANT), especially leukemia cells. The purpose of the present study was to evaluate the antioxidant properties and explore the antiproliferation impact and mechanism of EANT in leukemia cells. Five standard assays demonstrated that EANT exhibits antioxidant capability. In the cell line model, EANT dose-responsively inhibited cell viabilities of three leukemia cell lines (HL-60, K-562, and MOLT-4) based on 24 h MTS assays, which were reverted by pretreating oxidative stress and apoptosis inhibitors (N-acetylcysteine and Z-VAD-FMK). Due to similar sensitivities among the three cell lines, leukemia HL-60 cells were chosen for exploring antiproliferation mechanisms. EANT caused subG1 and G1 cumulations, triggered annexin V-detected apoptosis, activated apoptotic caspase 3/7 activity, and induced poly ADP-ribose polymerase expression. Moreover, reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization were generated by EANT, which was reverted by N-acetylcysteine. The antioxidant response to oxidative stress showed that EANT upregulated mRNA expressions for nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), thioredoxin (TXN), heme oxygenase 1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. Moreover, these oxidative stresses led to DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) and were alleviated by N-acetylcysteine. Taken together, EANT demonstrated oxidative stress-dependent anti-leukemia ability to HL-60 cells associated with apoptosis and DNA damage.

Aqueous extract of andean berry induces apoptosis in human colon cancer cells without mitochondrial damage

BACKGROUND: Andean berry contains several classes of phenolic compounds which have showed antioxidant and cytotoxic activity. OBJECTIVE: To characterize the Andean berry aqueous extract and to study their anti-proliferative mechanisms on SW480 and SW620 cell lines (human colon adenocarcinoma). METHODS: Total phenolic and total anthocyanins contents were determined by Folin-Ciocalteau and differential pH methods, respectively. Antioxidant activity was measured by FRAP, ORAC and DPPH methods. Antiproliferative effect was determined by sulforhodamine colorimetric method and apoptosis was analyzed by flow cytometry using propidium iodide/Annexin-V. Mitochondrial potential was evaluated using DIOC6 and ROS levels were measured by 2,7-Dicholorodihydrofluorescein diacetate (DCFH-DA). RESULTS: The total phenol and anthocyanin content were 4409.78± 63,05 mg equivalents of gallic acid/100 mL and 106,57± 1.43 mg equivalents of cyanidin-3-glycoside/100 mL, respectively. Andean berry extract showed antioxidant activity by FRAP, ORAC and DPPH methods and antiproliferative effect on SW480 and SW620 cells. It was observed a cell cycle arrest at S and G2/M phases on SW480 and at G0/G1 phase on SW620 cells. Aqueous extract did not induce mitochondrial depolarization or affect intracellular ROS levels. CONCLUSIONS: Andean berry aqueous extract has antioxidant capacity and induces apoptosis involving cell cycle arrest in SW480 and SW620 cells without mitochondrial damage.

Protective effect of propofol via the regulation of ovarian granulosa cell proliferation and apoptosis.

Propofol is an anesthetic frequently used in surgery. Accumulating evidence suggests that propofol exhibits an effect on cell viability, apoptosis and invasion in several types of cancer cells. MicroRNAs (miRNAs) have been reported to play pivotal roles in the development of polycystic ovary syndrome (PCOS). However, the diagnostic applications of miR-451a in PCOS remain unknown. The present study aimed to elucidate the effects of propofol on ovarian granulosa cell proliferation and apoptosis and illustrate the specific mechanisms associated with this process. Human ovarian granulosa cell-like KGN cells, which were used as a representative of granulosa cells in the present study, were treated with different concentrations (0, 1, 5 and 10 µg/ml) of propofol for 48 h and cell proliferation and apoptosis were assessed using MTT and flow cytometry assays, respectively. Propofol treatment resulted in significant inhibition of cell viability and induction of apoptosis in KGN cells, which was accompanied with increased cleaved caspase 3 and suppressed pro-caspase 3 expression levels. Furthermore, propofol reduced Wnt3a and β-catenin protein and mRNA expression levels. miR-451a expression in KGN cells was evaluated by reverse transcription-quantitative PCR (RT-qPCR). miR-451a expression was upregulated in propofol-stimulated KGN cells. The data further demonstrated that miR-451a mimics suppressed cell proliferation and increased apoptosis of KGN cells compared with cells transfected with control mimics. Furthermore, the association between miR-451a and propofol was investigated. Rescue experiments were performed to investigate the anti-proliferative mechanism of propofol in ovarian granulosa cells. KGN cells were transfected with miR-451a inhibitor or inhibitor control sequences for 6 h and treated with 10 µg/ml propofol for an additional 48 h. The results from the MTT, RT-qPCR and western blot assays indicated that 10 µg/ml propofol inhibited cell viability, induced apoptosis, enhanced cleaved caspase 3 expression, reduced pro-caspase 3 levels and inhibited the protein and mRNA expression of Wnt3a and β-catenin. However, inhibition of miR-451a demonstrated the opposite effects. In conclusion, the results of the present study revealed that propofol exerted an anti-proliferative and apoptosis-inducing role in ovarian granulosa cells through mediation of miR-451a expression. In addition, the data indicated that miR-451a may be used as an effective therapeutic target for PCOS treatment.

A Phase 2 Study Of Lenalidomide, Rituximab, Cyclophosphamide and Dexamethasone (LR-CD) For Untreated Low Grade Non-Hodgkin Lymphoma Requiring Therapy: Waldenström's Macroglobulinemia Cohort Results

BackgroundSingle agent therapy with the novel agent lenalidomide has shown efficacy in relapsed lymphomas, through anti-proliferative and immunomodulatory mechanisms, and may have a synergistic effect with rituximab. There is limited data on the efficacy and safety of lenalidomide in multidrug combinations in treatment naïve patients. We designed a phase II single arm trial of untreated low grade NHL patients with lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) to evaluate tumor response, toxicity (adverse events) and survival1. Initial analysis showed promising results in patients with lymphoplasmacytic lymphoma (WM), and the cohort was expanded for analysis. Lenalidomide has previously been studied with rituximab in this population but significant toxicity, mainly anemia (8/16 (50%) grade 2 and 1/16 (6%) grade 3), caused cessation of study enrollment2. We report here results of the Waldenström's macroglobulinemia cohort. MethodsEligibility: 18 years of age, untreated indolent NHL, ECOG PS ≤2, nodes ≥ 2cm by MRI or CT or IgM ≥ 400mg/dL, ANC >1400 mm³, platelet count ≥ 100,000/mm³, creatinine ≤ 2mg/dL. Treatment consisted of IV rituximab 375mg/m2 on day 1, oral lenalidomide 20mg days 1-21, cyclophosphamide 250mg/m2 days 1, 8, 15, and dexamethasone 40mg days 1, 8,15, 22, on a 28 day cycle. All patients received aspirin 325 mg daily. Treatment continued 2 cycles beyond best response up to a maximum of 12 cycles. Toxicity was assessed using NCI CTCAE v3.0. ResultsSixteen patients with lymphoplasmacytic lymphoma, with monoclonal IgM present at baseline, have enrolled at Mayo Clinic with 15 evaluated for toxicity and response (1 withdrew before treatment). Four patients are still receiving treatment. Patient characteristics: median age 69 (47-83), 87% male, 100% Caucasian, median IgM 4480 (1740-7890). At baseline 4/15 (27%) patients had grade 2 anemia and 2/15 (13%) had grade 3. Median number of cycles administered was 8, and 73% completed the study per protocol. Overall best response rate was 80%, 1 patient with CR and 11 with PR. The most common grade 3 or 4 adverse events were neutropenia (13% grade 3 and 33% grade 4), anemia (27% grade 3, 13% grade 4), and leukopenia (grade 3, 13%, grade 4, 20%). Six patients had grade 3 or higher nonhematologic toxicity. At a median follow up of 17 months (0.9-38.3), 11 patients had not progressed and 4 progressed. The median PFS is 24.9 months, and the OS at 2 years is 86%. One death secondary to relapsed disease occurred 7.7 months after completing 12 cycles of treatment. ConclusionsLR-CD can be safely administered in newly diagnosed symptomatic Waldenström's macroglobulinemia. The main toxicities are anemia and neutropenia, with more anemia (≥gr3 40% vs. 14%) than seen in other low grade histologies treated with LR-CD1. A prior study of lenalidomide and rituximab in WM was stopped due to the development of anemia suggesting that lenalidomide was not a safe or efficacious drug in this disease. However, while we did see anemia develop during therapy with LR-CD, 6/15 patients had grade≥2 anemia at baseline. Compared to historical results this highly active regimen deserves study in a randomized trial.1 Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 27412 Clin Cancer Res 2009; 355 15(1) January 1, 2009This trial is sponsored by Celgene Disclosures:Off Label Use: lenalidomide is not approved for treatment of waldenstrom macroglobulinemia. Nowakowski:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stewart:Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Fonseca:millennium: Consultancy; amgen: Consultancy; Binding site: Consultancy; onyx: Consultancy; medtronic: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; lilly: Consultancy; Onyx: Research Funding; cylene: Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids

Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1–10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50–7.67 μM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.

Pharmacokinetic properties and anti-proliferative mechanisms of vanillin against acute lymphoblastic leukemia (Jurkat) cells

The anti-proliferative potential of vanillin isolated from an ethnomedicine Flacourtia indica bark was evaluated in an acute lymphoblastic leukemia cell line (Jurkat) in our previous study, but its molecular mechanisms of action are not yet revealed. The present work investigated the pharmacokinetic properties & cellular uptake of vanillin, in addition to evaluating the effect of vanillin treatment on cell morphology, mitochondrial membrane potential, DNA fragmentation, and cell survival & pro-apoptotic proteins in Jurkat cells. High absorption, good oral bioavailability, and safety of vanillin were recorded through in silico pharmacokinetic studies. In vitro study results indicate that 24.07% of vanillin was absorbed by Jurkat cells within 120 min. The IC50 dose of vanillin reduced the mitochondrial membrane potential up to 77.05% and also caused 60.94% of DNA fragmentation in Jurkat cells. Further, inhibition of cell survival proteins such as H-RAS, K-RAS, N-RAS, & BCL-2 and activation of pro-apoptotic proteins like p-38, BAX, pro-caspase-9, pro-caspase-3, and caspase-3 by vanillin was confirmed through molecular docking and western blotting studies. Thus, the current study revealed the pharmacokinetic properties and anti-proliferative mechanisms of vanillin in Jurkat cells. Therefore vanillin could be further investigated to develop a safe and alternative phytopharmaceutical to treat acute lymphoblastic leukemia.

Fixed-Combination Halobetasol Propionate and Tazarotene in the Treatment of Psoriasis: Narrative Review of Mechanisms of Action and Therapeutic Benefits.

Psoriasis is a lifelong disease associated with cycles of remission and relapse. Topical treatments are the front line of psoriasis therapy for most patients and have antiproliferative, anti-inflammatory, and immunosuppressive mechanisms of action. Novel fixed-dose combinations of topical therapeutic agents are becoming increasingly available, leveraging multiple mechanisms of action to improve safety and efficacy with formulations that are easier to use and may allow for the use of lower doses of active ingredients. A fixed-combination lotion containing the potent-to-superpotent corticosteroid halobetasol propionate (HP) and the retinoid tazarotene (HP 0.01%/TAZ 0.045%) was recently developed using polymeric emulsion technology. This new formulation technology allows for more uniform and efficient delivery of the active ingredients at lower doses than conventional monotherapy formulations of either ingredient while providing enhanced hydration and moisturization. This review provides an up-to-date overview of the therapeutic mechanisms of action of HP and TAZ, the rationale behind the development of HP 0.01%/TAZ 0.045% lotion, and clinical trials data on the efficacy, safety and tolerability, and maintenance of therapeutic effect with HP 0.01%/TAZ 0.045% lotion in the treatment of moderate-to-severe plaque psoriasis.

Manuka honey enhanced sensitivity of HepG2, hepatocellular carcinoma cells, for Doxorubicin and induced apoptosis through inhibition of Wnt/\u03b2-catenin and ERK1/2

BackgroundRecently, there is increasing awareness focused on the identification of naturally occurring anticancer agents derived from natural products. Manuka honey (MH) has been recognized for its biological properties as antimicrobial, antioxidant, and anticancer properties. However, its antiproliferative mechanism in hepatocellular carcinoma is not investigated. The current study focused mainly on investigating the molecular mechanism and synergistic effect of anticancer properties of MH on Doxorubicin (DOX)-mediated apoptotic cell death, using two different p53 statuses (HepG2 and Hep3B) and one non-tumorigenic immortalized liver cell line.ResultsMH treatment showed a proliferative inhibitory effect on tested cells in a dose-dependent manner with IC50 concentration of (6.92 ± 0.005%) and (18.62 ± 0.07%) for HepG2 and Hep3B cells, respectively, and induced dramatic morphological changes of Hep-G2 cells, which considered as characteristics feature of apoptosis induction after 48 h of treatment. Our results showed that MH or combined treatments induced higher cytotoxicity in p53-wild type, HepG2, than in p53-null, Hep3B, cells. Cytotoxicity was not observed in normal liver cells. Furthermore, the synergistic effect of MH and Dox on apoptosis was evidenced by increased annexin-V-positive cells and Sub-G1 cells in both tested cell lines with a significant increase in the percentage of Hep-G2 cells at late apoptosis as confirmed by the flow cytometric analysis. Consistently, the proteolytic activities of caspase-3 and the degradation of poly (ADP-ribose) polymerase were also higher in the combined treatment which in turn accompanied by significant inhibitory effects of pERK1/2, mTOR, S6K, oncogenic β-catenin, and cyclin D1 after 48 h. In contrast, the MH or combined treatment-induced apoptosis was accompanied by significantly upregulated expression of proapoptotic Bax protein and downregulated expression of anti-apoptotic Bcl-2 protein after 48 h.ConclusionsOur data showed a synergistic inhibitory effect of MH on DOX-mediated apoptotic cell death in HCC cells. To our knowledge, the present study provides the first report on the anticancer activity of MH and its combined treatment with DOX on HCC cell lines, introducing MH as a promising natural and nontoxic anticancer compound.

Phase 1b/2 SEASTAR trial: Safety, pharmacokinetics, and preliminary efficacy of the poly(ADP)-ribose polymerase (PARP) inhibitor rucaparib and angiogenesis inhibitor lucitanib in patients with advanced solid tumors.

3102 Background: Lucitanib is an oral, potent tyrosine kinase inhibitor that selectively inhibits VEGFR1–3, PDGFRα/β, and FGFR1–3. In preclinical studies, antitumor activity of rucaparib is enhanced by lucitanib through antiproliferative, antiangiogenic, and immunological mechanisms. We hypothesize that combining lucitanib and rucaparib is tolerable and can induce a higher hypoxic state and homologous recombination repair deficiency that may lead to greater sensitivity to PARP inhibition. Methods: Patients with advanced solid tumors who had ≥1 prior line of therapy were eligible. Patients with BRCA1/2-mutated ovarian cancer must have received prior PARP inhibitor. Rucaparib and lucitanib were escalated using a 3+3 phase 1b dose-escalation design from starting doses of 300 mg BID and 4 mg QD, respectively. Dose-limiting toxicities (DLTs) were assessed during the first 28 days of treatment. Plasma samples were collected for pharmacokinetic analyses. Genomic alterations were identified by local testing, or through central testing of plasma or tumor tissue. Results: As of February 1, 2021, 16 patients were treated with rucaparib + lucitanib and included in the analyses (Table). Patients had a median of 4 prior therapies; 1 patient had prior PARP inhibitor (olaparib) treatment. Median time on treatment was 58.5 days, with 2 patients ongoing as of the data cutoff date. A DLT of grade 3 proteinuria was seen in Cohort 1; no other DLTs have been reported. Across all cohorts, the most common any-grade treatment-emergent adverse events were nausea (n=9; grade ≥3, n=1), hypertension (n=8; grade ≥3, n=2) and ALT/AST increased (n=7; grade ≥3, n=3). Initial pharmacokinetic data indicated no drug interactions between the 2 agents. To date, 1 patient in Cohort 1 with PALB2-mutated advanced endometrial cancer had a confirmed partial response per RECIST v1.1, lasting 30 weeks; 6 patients had RECIST v1.1 stable disease (SD), including 1 patient each in Cohorts 1 and 3 with SD for ≥16 weeks. In addition, 1 patient in Cohort 2 with BRCA2-mutated castration-resistant prostate cancer continued to receive treatment despite initial progressing bone metastases, resulting in a prostate-specific antigen response (≥50% change) lasting 16 weeks and a best change in sum of target lesions of −46.3%. Conclusions: Initial findings suggest that rucaparib + lucitanib has an acceptable safety profile. The safety and efficacy of the combination are being further evaluated. Clinical trial information: NCT03992131. [Table: see text]

Beneficial Effects of Green Tea Catechins on Female Reproductive Disorders: A Review.

Tea is one of the most widely consumed beverages worldwide after water, and green tea accounts for 20% of the total tea consumption. The health benefits of green tea are attributed to its natural antioxidants, namely, catechins, which are phenolic compounds with diverse beneficial effects on human health. The beneficial effects of green tea and its major bioactive component, (−)-epigallocatechin-3-gallate (EGCG), on health include high antioxidative, osteoprotective, neuroprotective, anti-cancer, anti-hyperlipidemia and anti-diabetic effects. However, the review of green tea’s benefits on female reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis and dysmenorrhea, remains scarce. Thus, this review summarises current knowledge on the beneficial effects of green tea catechins on selected female reproductive disorders. Green tea or its derivative, EGCG, improves endometriosis mainly through anti-angiogenic, anti-fibrotic, anti-proliferative and proapoptotic mechanisms. Moreover, green tea enhances ovulation and reduces cyst formation in PCOS while improving generalised hyperalgesia, and reduces plasma corticosterone levels and uterine contractility in dysmenorrhea. However, information on clinical trials is inadequate for translating excellent findings on green tea benefits in animal endometriosis models. Thus, future clinical intervention studies are needed to provide clear evidence of the green tea benefits with regard to these diseases.