Action Of Anticancer Drugs Research Articles

Development of Nanocarrier-Based Radionuclide and Photothermal Therapy in Combination with Chemotherapy in Melanoma Cancer Treatment.

Conventional cancer therapy methods have serious drawbacks that are related to the nonspecific action of anticancer drugs that leads to high toxicity on normal cells and increases the risk of cancer recurrence. The therapeutic effect can be significantly enhanced when various treatment modalities are implemented. Here, we demonstrate that the radio- and photothermal therapy (PTT) delivered through nanocarriers (gold nanorods, Au NRs) in combination with chemotherapy in a melanoma cancer results in complete tumor inhibition compared to the single therapy. The synthesized nanocarriers can be effectively labeled with 188Re therapeutic radionuclide with a high radiolabeling efficiency (94-98%) and radiochemical stability (>95%) that are appropriate for radionuclide therapy. Further, 188Re-Au NRs, mediating the conversion of laser radiation into heat, were intratumorally injected and PTT was applied. Upon the irradiation of a near-infrared laser, dual photothermal and radionuclide therapy was achieved. Additionally, the combination of 188Re-labeled Au NRs with paclitaxel (PTX) has significantly improved the treatment efficiency (188Re-labeled Au NRs, laser irradiation, and PTX) compared to therapy in monoregime. Thus, this local triple-combination therapy can be a step toward the clinical translation of Au NRs for use in cancer treatment.

Education Aimed at Patient Safety Management of Chemotherapy Conducted at University Education Sites

The School Education Law was revised in 2006, and the university pharmacy education system and the national pharmacist examination system were changed. In line with the advancement of medical technology and the division of labor, 16 years have passed since the length of undergraduate pharmacy education was extended from 4 to 6 years in order to foster highly qualified pharmacists. During this period, the curriculum for practical training has been revised, and lectures and exercises focused on clinical education have been incorporated to foster pharmacists who can be useful in the medical field. In the area of cancer drug therapy, the university provides students with opportunities to learn about the basic mechanisms of action and side effects of anticancer drugs, but there is little coverage of clinical guidelines and pharmacological management of the latest therapies, such as cancer immunotherapy. Prior to my arrival at Hoshi University, I was involved in clinical work and clinical research at an oncology hospital for 13 years. Since my arrival, I have been exploring the gap between oncology pharmacotherapy and pharmacy education, and have been working to fill it. We have incorporated new curricula, such as exercises in formulation suggestions, lectures to deepen understanding of guidelines and supportive care, and information on the latest cancer drug therapies, such as cancer immunotherapy. This paper outlines the pharmacy education required to produce pharmacists who can practice safe cancer drug therapy.

Analysis of metabolites and metabolism-mediated biological activity assessment of ginsenosides on microfluidic co-culture system.

In vivo, the complex process of drugs metabolism alters the change in drug composition and determines the final pharmacological properties of oral drugs. Ginsenosides are primary constituents of ginseng, whose pharmacological activities are greatly affected by liver metabolism. However, the predictive power of existing in vitro models is poor due to their inability to mimic the complexity of drug metabolism in vivo. The advance of organs-on-chip-based microfluidics system could provide a new in vitro drug screening platform by recapitulating the metabolic process and pharmacological activity of natural product. In this study, an improved microfluidic device was employed to establish an in vitro co-culture model by culturing multiple cell types in compartmentalized microchambers. Different cell lines were seeded on the device to examine the metabolites of ginsenosides from the hepatocytes in top layer and its resulting efficacy on the tumors in bottom layer. Metabolism dependent drug efficacy of Capecitabine in this system demonstrated the model is validated and controllable. High concentrations of CK, Rh2 (S), and Rg3 (S) ginsenosides showed significant inhibitory effects on two types of tumor cells. In addition, apoptosis detection showed that Rg3 (S) through liver metabolism promoted early apoptosis of tumor cells and displayed better anticancer activity than prodrug. The detected ginsenoside metabolites indicated that some protopanaxadiol saponins were converted into other anticancer aglycones in varying degrees due to orderly de-sugar and oxidation. Ginsenosides exhibited different efficacy on target cells by impacting their viabilities, indicating hepatic metabolism plays an important role in determining ginsenosides efficacy. In conclusion, this microfluidic co-culture system is simple, scalable, and possibly widely applicable in evaluating anticancer activity and metabolism of drug during the early developmental phases of natural product.

Cisplatin binding to angiogenin protein: new molecular pathways and targets for the drug's anticancer activity.

Cisplatin (CisPt), a platinum-based chemotherapeutic widely used in the treatment of various cancers, has multiple mechanisms of action, including nuclear DNA (nDNA) and mitochondrial DNA (mDNA) damage and cytoskeletal perturbations affecting, in turn, the membrane transporter activity. CisPt binding to proteins and enzymes may modulate its biochemical mechanism of action and is associated with cancer cell resistance to the drug. In this work, we investigate the interaction between cisplatin and angiogenin (Ang), a protein strongly expressed in many types of cancer and a potent angiogenic factor. The adduct formed upon reaction of CisPt with Ang (Ang@CisPt) was characterized by X-ray crystallography to evidence the exact platination site and by UV-visible (UV-vis) absorption and circular dichroism (CD) spectroscopies to shed light on any possible change in the protein conformation. Furthermore, high-resolution electrospray ionization (ESI) mass spectrometry was utilized to evaluate the Ang : CisPt stoichiometry of the Ang@CisPt adduct. The effect of the Ang@CisPt adduct on a prostate cancer cell line (PC-3) was tested by colorimetric assays in terms of cell viability, at both levels of nuclear and mitochondrial damage, and reactive oxygen species (ROS) production. Cellular imaging by laser scanning confocal microscopy (LSM) was utilized to scrutinize the cytoskeleton actin reorganization and the lysosome and mitochondria organelle perturbation. These studies highlight the possibility of new molecular pathways and targets for CisPt activity.

Synergistic Combinatorial effect of L-asparaginase and Trastuzumab against HER2+ breast cancer cells

Multi-targeted drug combinations which selectively inhibit the proliferation of cancer cells are required for effective anticancer treatment. The current anti-HER2 positive breast cancer therapy involves Trastuzumab and doxorubicin drug combination which produces toxic side effects in clinical settings including high cardiotoxicity. In this study, anticancer activity of single drug as well as the drug combination effect of L-asparaginase (Celginase) and Trastuzumab (Herceptin) was studied on HER2 positive breast cancer (SKBR3) cells. Inhibition of cell proliferation assay based on fluorescence readout was studied to estimate the anticancer effect of the drugs. HUVEC cells were used as negative control cells. Individually as a single drug, Trastuzumab (Herceptin) and L-asparaginase (Celginase) showed anticancer activity against SKBR3 cells with IC50 value of 0.031ng/ml and 1.168µg/ml respectively. The drug combination interaction of Trastuzumab and L-asparaginase resulted in combination index of less than 1(CI < 1) showing their synergistic effect against SKBR3 cells. No cytotoxic effect was observed in control HUVEC cells. The results suggested that the antitumor activity of Trastuzumab and L-asparaginase against HER2 positive breast cancer was found specific to HER2 positive cancer (SKBR3) cells. This synergistic drug interaction of L-asparaginase and Trastuzumab could be further explored to as an alternative to current drug combination therapy against the HER2 positive breast cancer.

Binary and ternary inclusion complexation of lapatinib ditosylate with β-cyclodextrin: preparation, evaluation and in vitro anticancer activity

BackgroundLapatinib ditosylate, an efficient tyrosine kinase inhibitor for breast cancer, poses pharmacokinetic issues, hence developing its oral delivery system is troublesome. The poor aqueous solubility of this medicament is a key impediment in developing its successful formulation. So, the current study aims to improve water solubility of Lapatinib ditosylate by using complexation technique with β-cyclodextrin and a suitable ternary agent.ResultsBinary and ternary complexes of Lapatinib ditosylate were synthesized by means of kneading and lyophilization using β-cyclodextrin and PVP K30. As a ternary agent, various hydrophilic polymers, as well as organic acids, were assessed, and PVP K30 was chosen for the final formulation based on its stability constant and complexation efficiency. When compared to pure Lapatinib ditosylate, both inclusion complexes demonstrated improved solubility, and drug dissolution. Differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), Fourier transform infrared (FTIR), and scanning electron microscopic (SEM) techniques, all validated the complex formation. Docking studies picturized the geometry of Lapatinib ditosylate in β-cyclodextrin cavity. Using MCF-7 cell lines, investigation of anticancer activity of the pure drug and its synthesized complexes was carried out and the results revealed that the complexes had stronger anticancer activity than Lapatinib ditosylate alone.ConclusionsOverall, it can be concluded that Lapatinib ditosylate complexation increased its aqueous solubility, resulting in its increased dissolution and in vitro anticancer activity in a breast cancer cell line.

A REVIEW ON PHARMACOGENOMICS AND ITS IMPACT IN THE DEVELOPMENT OF HEALTHCARE SYSTEM

Pharmacogenomics is the study of genomics/genetics and proteomics. It is the field of science which can make the goal of personalised medicine possible. This review article briefly explains about various genes associated with therapeutic activity of various Anti-cancer and Anti-reteroviral drugs in humans. The need to perform PGx test to find the ADR’s of these drugs and narrowing of these drugs which are used for the treatment of these diseases especially during their lethal stages . this is an critical review on why same drugs in same doses have different effects in different persons and how this field has been used in various health care systems over the period of time was described. This presentation also emphasizes the scope of pharmacogenomics in improving health care system. KEYWORDS :-Pharmacogenomics, Pharmacogenomic test (PGx test) ,Biomarkers of Anti-cancer and Anti-reteroviral drugs, Personalised medicine, Genetic polymorphism

Discovery of New Glucose Uptake Inhibitors as Potential Anticancer Agents by Non-Radioactive Cell-Based Assays.

Tumor cells rely on aerobic glycolysis to support growth and survival, thus require more glucose supply. Glucose transporters GLUTs, primarily GLUT1, are overexpressed in various cancers. Targeting GLUTs has been regarded as a promising anticancer strategy. In this study, we first evaluated 75 potential GLUT1 inhibitors obtained from virtual screening of the NCI chemical library by a high-throughput cell-based method using a fluorescent glucose analogue 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy-d-glucose (2-NBDG) in COS-7 and SKOV3 cells that express high levels of GLUT1. Four compounds, #12, #16, #43 and #69, that significantly inhibited glucose uptake were further evaluated using flow cytometry directly measuring 2-NBDG uptake at the single-cell level and a Glucose Uptake-GloTM assay indirectly measuring 2-deoxy-d-glucose uptake in SKOV3, COS-7 or MCF-7 cells. The inhibitory effect on cancer cell growth was also determined in SKOV3 and MCF-7 cells, and #12 exhibited the best growth inhibitory effect equivalent to a known GLUT1 inhibitor WZB117. Although the anticancer effect of the identified potential GLUT1 inhibitors was moderate, they may enhance the activity of other anticancer drugs. Indeed, we found that #12 synergistically enhanced the anticancer activity of metformin in SKOV3 ovarian cancer cells.

Nanotherapy based on magneto-mechanochemical modulation of tumor redox state.

Magnetic nanoparticles (MNs) are typically used as contrast agents for magnetic resonance imaging or as drug carriers with a remotely controlled delivery to the tumor. However, they can also potentiate the action of anticancer drugs under the influence of applied constant magnetic (CMFs) and electromagnetic fields (EMFs). This review demonstrates the role of magneto-mechanochemical effects produced by MNs alone and loaded with anticancer agents (MNCs) in response to CMFs and EMFs for modulation of tumor redox state. The combined treatment is suggested to act by two mechanisms: spin-dependent electron transport propagates free radical chain reactions, while magnetomechanical interactions cause conformational changes in drug molecules loaded onto MNs and generate reactive oxygen species (ROS). By adjusting the parameters of CMFs and EMFs during the magneto-mechanochemical synthesis and subsequent treatment, it is possible to modulate ROS production and switch redox signaling involved in ERK1/2 and NF-κB pathways from initiation of tumor growth to inhibition. Observations of tumor volume in different animal models and treatment combinations reported a 6%-70% reduction as compared with conventional drugs. Despite these results, there is a general lack of research in magnetic nanotheranostics that link redox changes across multiple levels of organization in the tumor-bearing host. Further multidisciplinary studies with more focus on the relationship between the electron transport processes in biomolecules and their effects on the tumor-host interaction should accelerate the clinical translation of magnetic nanotheranostics. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Probing Alterations in MDM2 Catalytic Core Structure Effect of Garcinia Mangostana Derivatives: Insight from Molecular Dynamics Simulations.

The MDM2-p53 protein-protein interaction is a promising model for researchers to design, study, and discover new anticancer drugs. The design of therapeutically active compounds that can maintain or restore the binding of MDM2 to p53 has been found to limit the oncogenic activities of both. This led to the current development of a group of xanthone-core and cis-imidazoline analogs compounds, among which γ-Mangostin (GM), α-Mangostin (AM), and Nutlin exhibited their MDM2-p53 interaction inhibitory effects. Therefore, in this study, we seek to determine the mechanisms by which these compounds elicit MDM2-p53 interaction targeting. Unique to the binding of GM, AM, and Nutlin, from our findings, they share the same three active site residues Val76, Tyr50, and Gly41, which represent the top active side residues that contribute to high electrostatic energy. Consequently, the free binding energy contributed enormously to the binding of these compounds, which culminated in the high binding affinities of GM, AM, and Nutlin with high values. Furthermore, GM, AM, and Nutlin commonly interrupted the stable and compact conformation of MDM2 coupled with its active site, where Cα deviations were relatively high. We believe that our findings would assist in the design of more potent active anticancer drugs.

In vitro Evaluation of Antigenotoxic Effects of Phloridzin

Phytochemicals have a vast number of properties contributing to human health by acting on numerous different mechanisms. Phloridzin, a phytochemical mainly found in Malus species, possesses diverse biological activities including anti-diabetic and antioxidative activities. Here, our aim is to explore antigenotoxic potential and proliferative effects of phloridzin on human lymphocytes in vitro by employing chromosome aberration, micronucleus and comet assays. Mitomycin C, both an anticancer and genotoxic agent, was utilized to induce genotoxicity. Phloridzin significantly suppressed the genotoxic effects of mitomycin C at 125-500 µg/mL concentrations in all assays used (p < 0.05). We also revealed that phloridzin and mitomycin C combination had a significantly negative effect on mitotic index (p < 0.05), whereas in general, gender differences did not play a role in manifestation of neither antigenotoxic nor antiproliferative activities of the combination.These results suggest that phloridzin is an antigenotoxic compound and its consumption may interfere with the activity of anticancer drugs that exert their effects based on genotoxic mechanisms.

Phytochemical investigation, antioxidant and anticancer activities of various Unani drugs.

To analyze the phytochemicals, antioxidant, and anticancer activities on MCF-7 human breast cancer cell line using aqueous, hydro-ethanol, and methanol extracts of different Unani drugs, e.g., Halela Siyah, Aftimoon, Bisfayej, Ustukhudoos, and Kutki. The qualitative examination (alkaloids, terpenoids, tannins, and saponins), anticancer activity, and an antioxidant assay of the three different extracts were done by MTT assay and DPPH assay, respectively, using different Unani drugs. The qualitative examination confirmed the substantive presence of phytochemical constituents in all the extracts of these drugs. The Methanolic extract of Halela Siyah had the highest DPPH scavenging activity (91%), while Bisfayej had the lowest (58%). Similarly, the hydro-ethanolic extract showed approximately identical activity for Halela Siyah (89%), Aftimoon (88%), Bisfayej (84%), Kutki (82%), and Ustukhudoos (81%). The aqueous extracts of Halela Siyah (88%) had the highest DPPH scavenging activity, whereas Bisfayej (73%) had the lowest. The methanolic extract of Aftimoon demonstrated the greatest anticancer activity (IC50- 108), while Aftimoon showed the least activity (IC50- 316). Halela Siyah (IC50- 175) and Aftimoon (IC50- 178) showed substantially the same activity in aqueous extracts. Ustukhudoos hydro-ethanol extracts had the highest (IC50- 130) activity, whereas Aftimoon had the lowest (IC50- 204). In conclusion, our findings evaluated the presence of phytochemicals, good antioxidant activity, and anticancer activity in different extracts of drugs used in this study. The study shows these drugs have potential anticancer activity against breast cancer in MCF-7 cell lines.

Advancement and recent trends in seeking less toxic and more active anti-cancer drugs: Insights into thiourea based molecules

The finding of potent anticancer agents with low toxicity and high selectivity has remained valuable for human health. Thiourea derivatives are the most significant organic compounds with integral and typical characteristics of numerous varieties of natural products and pharmaceutical agents. It exhibits various pharmacological properties, and its analogues confer a great deal of structural diversity that was proven to be the most advantageous in the search for novel therapeutic agents. Thiourea derivatives, which show beneficial antitumor activities, are typically considered the central core in various anticancer derivatives. They also have broad-ranging biological activities such as anti-inflammatory, antibacterial, antifungal, antitubercular, antihypertensive, antihistaminic, and antiviral activities. Several FDA-approved drugs of thiourea derivatives and their analogues in the market, currently in progress through various registration statuses or clinical stages, indicating that thiourea derivatives are the most promising drugs. The current review is intended to systematically provide comprehensive evidence in the recent developments of thiourea to treat numerous types of cancer. Furthermore, we hope that this review will be helpful for novel consideration in seeking rational designs of less toxic and more active drugs and more effective diagnostics agents.

The Mechanistic Understanding of RAD51 Defibrillation: A Critical Step in BRCA2-Mediated DNA Repair by Homologous Recombination

The cytotoxic action of anticancer drugs can be potentiated by inhibiting DNA repair mechanisms. RAD51 is a crucial protein for genomic stability due to its critical role in the homologous recombination (HR) pathway. BRCA2 assists RAD51 fibrillation and defibrillation in the cytoplasm and nucleus and assists its nuclear transport. BRC4 is a peptide derived from the fourth BRC repeat of BRCA2, and it lacks the nuclear localization sequence. Here, we used BRC4 to (i) reverse RAD51 fibrillation; (ii) avoid the nuclear transport of RAD51; and (iii) inhibit HR and enhance the efficacy of chemotherapeutic treatments. Specifically, using static and dynamic light scattering, transmission electron microscopy, and microscale thermophoresis, we show that BRC4 eroded RAD51 fibrils from their termini through a “domino” mechanism and yielded monomeric RAD51 with a cumulative nanomolar affinity. Using cellular assays (BxPC-3, pancreatic cancer), we show that a myristoylated BRC4 (designed for a more efficient cell entry) abolished the formation of nuclear RAD51 foci. The present study provides a molecular description of RAD51 defibrillation, an essential step in BRCA2-mediated homologous recombination and DNA repair.

Unveiling the mechanism of action of nature-inspired anti-cancer compounds using a multi-omics approach

The 2020 global cancer registry has ranked breast cancer (BCa) as the most commonly diagnosed type of cancer and the most common cause of cancer-related deaths in women worldwide. Increasing resistance and significant side effects continue to limit the efficacy of anti-BCa drugs, hence the need to identify new drug targets and to develop novel compounds to overcome these limitations. Nature-inspired anti-cancer compounds are becoming increasingly popular since they often provide a relatively safe and effective alternative. In this study, we employed multi-omics techniques to gain insights into the relevant mechanism of action of two recently identified new nature-inspired anti-cancer compounds (SIMR3066 and SIMR3058). Discovery proteomics analysis combined with LC-MS/MS-based untargeted metabolomics analysis was performed on compound-treated vs DMSO-treated (control) MCF-7 cells. Downstream protein functional enrichment analysis showed that most of the responsive proteins were functionally associated with antigen processing and neutrophil degranulation, RNA catabolism and protein folding as well as cytoplasmic vesicle lumen and mitochondrial matrix formation. Consistent with the proteomics findings, metabolomic pathway analysis suggested that the differentially abundant compounds indicated altered metabolic pathways such as glycolysis, the Krebs cycle and oxidative phosphorylation. Furthermore, metabolomics-based enriched-for-action pathway analysis showed that the two compounds associate with mercaptopurine, thioguanine and azathioprine related pathways. Lastly, integrated proteomics and metabolomics analysis revealed that treatment of BCa with SIMR3066 disrupts several signaling pathways including p53-mediated apoptosis and the circadian entertainment pathway. Overall, the multi-omics approach we used in this study indicated that it is a powerful tool in probing the mechanism of action of lead drug candidates. SignificanceIn this study we adopted a multi-omics (proteomics and metabolomics) strategy to learn more about the molecular mechanisms of action of nature-inspired potential anticancer drugs. Following treatment with SIMR3066 or SIMR3058, the integration of these multi-omics data sets revealed which biological pathways are altered in BCa cells. This study demonstrates that combining proteomics with metabolomics is a powerful method to investigate the mechanism of action of potential anticancer lead drug candidates.

Abstract 5475: DNA methylation regulator cordycepin suppresses gastric and colorectal cancer in combination with chemotherapy

Abstract Gastric cancer and colorectal cancer are the fifth and third most frequent malignant tumors, respectively. One of the most prevalent epigenetic characteristics in gastric and colorectal cancer is aberrant hypermethylation in the promoter of numerous tumor suppressor genes. Hypermethylation of the promoter inactivates tumor suppressor expression and contributes to tumor progression. DNA methyltransferases (DNMTs), which mediate DNA hypermethylation, are putative drug targets of cancer therapy. Several DNMTs inhibitors are under development. 5’-azacytidine and decitabine have been approved for the treatment of AML, myelodysplastic syndrome, and CMML. Clinical trials investigating DNMTs inhibitors in combination with other drugs are ongoing. However, clinical use of 5’-azacytidine and decitabine has been limited due to their toxicity. We have ever demonstrated that cordycepin, a major ingredient of Chinese traditional medicine Cordyceps, has activity of DNMTs inhibition. Treating cancer cells reversed hypermethylation of some tumor suppressor genes promoter, reactivated gene expression, and inhibited cancer cell proliferation. Here, we report the preclinical anti-cancer efficacy of Cordycepin in colorectal and gastric cancers in combination with chemotherapy drugs. In SGC-7901 human gastric cancer cells derived nude mice xenograft tumor model, mice were dosed 20mg/kg Cordycepin alone, 400mg/kg Capecitabine alone, or in combination orally, once daily, for 14 days. Tumor Growth Inhibition rate (TGI) of 89.2% was achieved in the combination therapy group comparing to 57.8% in the 400mg/kg Capecitabine mono-therapy group, and less than 10% in the Cordycepin alone group. Additionally, 20mg/kg Cordycepin plus 3mg/kg fluorouracil achieved TGI of 81.3% after 28 days of treatment in this model, comparing to 67.5% in the 6mg/kg fluorouracil monotherapy group. In HT-29 human colorectal cancer cells derived xenograft model, 20mg/kg Cordycepin plus 250mg/kg Capecitabine orally dosed once daily for 14 days showed TGI of 72.6%, similar to that treated by 400mg/kg Capecitabine alone (80.1%). 20mg/kg Cordycepin plus 2.5mg/kg Tegafur/Gimeracil/Oteracil once daily for 14 days had TGI of 76.7%, while 5mg/kg Tegafur/Gimeracil/Oteracil alone treatment group had TGI of 66.1%. 20mg/kg Cordycepin alone treatment showed only weak inhibition of tumor growth. Synergistic effects of Cordycepin and chemotherapy drugs were observed in treating both tested tumor models. Better tolerance was also shown in the combination therapy groups, as indicated by the mice body weight change. It is demonstrated that the DNMTs regulator Cordycepin has improved the anti-cancer activity and tolerance of chemotherapy drugs, such as Capecitabine, 5-FU, Tegafur/Gimeracil/Oteracil. Clinical development of Cordycepin and chemotherapy combination for cancer patients is strongly supported. Citation Format: Qing Dong, Yangze Cao, Jianyu Liu, Yang Qin. DNA methylation regulator cordycepin suppresses gastric and colorectal cancer in combination with chemotherapy [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 5475.

Phenolic and terpene compounds from Plectranthus amboinicus (Lour.) Spreng. Act as promising hepatic anticancer agents screened through in silico and in vitro approaches

The present study aims to validate the anticancer potential of the phytocompounds namely carvacrol, thymol, alpha pinene, limonene, vanillin, cineole and syringic acid against apoptotic regulator target proteins through in silico approach. The drug likeness nature of the selected phytocompounds analyzed using SWISS ADME online server. The phytocompounds met the requirements of Lipinski, Ghose, Veber, Egan, and Muegge rules of violations and expected to be orally available. The phytocompounds pervading zero violations were further subjected to predict the various pharmacokinetic properties such as Adsorption, Distribution, Metabolism, Excretion and Toxicity (ADMET). The phytocompounds possess good ADMET properties and can be considered safe and further developed into active commercial anticancer drugs. Molecular docking analysis revealed that the phytocompounds displayed strong interactions with the apoptotic regulator target proteins (PDB IDs 3MK8, 3PK1, 4IDT, 4ZBF, 5FMI, 5LAY and 5MW7) and illustrated good binding affinity in the range of -4.8 to -6.7Kcal/mol. The phytocompound carvacrol shows good binding affinity with all target proteins (-5.3 to -6.7 Kcal/mol) thereby possessing appreciable bonded and non-bonded interactions with the binding pockets of target proteins. Thymol and syringic acid possess good interaction with the cancer target proteins next to carvacrol. Density Functional Theory (DFT) analysis demonstrated the high softness, low hardness and less energy gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and revealed the molecular stability and reactivity of the phytocompounds. Drug ability likeliness property studied against GPCR ligands, ion channel modulators, kinase inhibitors, nuclear receptor ligands, protease inhibitors and enzyme inhibitors predicted the moderate biological activity of the phytocompounds. MTT assay confirmed 50% reduction of HEK 293 cells in a dose-dependent mode and the CC50 value was recorded as 27.56μg/ml and 15.32μg/ml for the methanolic extract and the drug avastin respectively. Thus the findings of the in silico based studies demonstrated the promising apoptosis - modulating effect of the phytocompounds and fetch novel improvements for alternative medicine in the prevention and treatment of hepatic cancer.

Epitheliod hemagioendothelioma (EHE) patient-derived model (PDX): Drug activity assessment and validation of novel biomarkers.

11566 Background: EHE is an ultra-rare sarcoma marked by two specific fusions, WWTR1-CAMTA1 (̃90%) and YAP1-TFE3 (̃10%). The clinical course of EHE ranges from indolent to highly aggressive, often associated with systemic paraneoplastic symptoms. Molecular predictors of clinical outcome are unknown. While surgery is the mainstay of treatment in the localized setting, management of advanced disease is challenging due to the rarity and poor sensitivity to conventional chemotherapy. This hampers the conduct of large prospective clinical trials. We report herein the first available EHE PDX (developed at the Istituto Nazionale Tumori, Milan, Italy) (INT), to assess the activity of old and new anticancer agents in EHE and inform future clinical studies. We also report on the preliminary results of a prospective observational study, ongoing in collaboration with The EHE Rare Cancer Charity (UK) and The EHE Foundation (US) aimed at identifying prognostic factors. Methods: A PDX of EHE in SCID mice was generated at INT from a patient (pt) suffering with the aggressive clinical variant, presenting with systemic symptoms. The PDX fully reproduces the originating clinical tumor in terms of morphology, biology ( WWTR1- CAMTA1 positive), overall transcriptomic profile. 2D (monolayer) and 3D (sferoids) cell cultures were established following PDX disaggregation. We have started assessing the comparative activity of currently available drugs (doxorubicin, sirolimus), while the efficacy of novel agents is undergoing. In parallel, we analyzed the presence of a selection of inflammatory cytokines in prospectively collected blood samples from EHE pts who entered an international observational study and we looked at their presence and modulation in the PDX model. Results: PDX experiments showed almost negligible activity of doxorubicin while sirolimus induced an 80% tumor volume inhibition. Biochemical analysis in tumors explanted from sirolimus-treated mice confirmed the down-regulation of mTOR downstream signaling. Among all cytokines, Growth and Differentiation Factor-15 (GDF-15) was found significantly over-expressed in serum of EHE pts (n = 23), particularly those with the most aggressive clinical variant, compared to healthy subjects (n = 23; p< 0.01). Consistently, EHE PDX and cell culture were found to release in the blood/culture medium GDF-15. Sirolimus was found to down-regulate GDF-15 release in both in vivo and in vitro EHE models. Conclusions: Our preliminary results indicate that this EHE PDX model is suitable i) for comparatively assessing the activity of anticancer drugs, and ii) for identifying and pre-clinically validating novel biomarkers. The role of GDF-15 in EHE progression deserves further investigation.

Assessment of antitumor activity of BP-C1, a platinum-based anticancer agent with a lignin-derived polymeric ligand, in autochthonous induced and spontaneous carcinogenesis rodent models

BackgroundA standard approach to study the anticancer activity of novel drugs is their testing in animals with inoculated tumors, which has some limitations. An alternative is the use of spontaneous or carcinogen-induced tumor models as they have better translation potential. The carcinogen-induced and transgenic tumor models were used to assess the antitumor activity of BP-C1, a platinum-containing drug with lignin-derived polymeric ligand. MethodsWe used female Swiss-H-derived mice and Wistar female rats to induce autochthonous tumors via exposure to benzo[a]pyrene and 1,2-dimethylhydrazine, respectively. Additionally, transgenic HER-2/neu FVB/N female mice, prone to the development of spontaneous mammary carcinomas, were used. ResultsAntitumor activity of BP-C1 was observed in soft tissue sarcomas, induced by benzo[a]pyrene. The animals treated with BP-C1 exhibited more stabilizations and therapy responses compared to placebo controls. The efficacy of BP-C1 was somewhat reduced compared to cyclophosphamide; however, their combination resulted in an enhanced antitumor effect. For the 1,2-dimethylhydrazine-induced rat colon cancer model, BP-C1 reduced tumor multiplicity by 21–41 %. For mammary adenocarcinomas in HER-2/neu FVB/N mice, short-termed complete responses were observed in the BP-C1 groups with a frequency of 12–13 %, while complete responses were absent in the placebo group. ConclusionThe results acquired indicated a wide spectrum of antitumor activity of BP-C1.

Lycopene in Combination With Sorafenib Additively Inhibits Tumor Metastasis in Mice Xenografted With Lewis Lung Carcinoma Cells.

Cancer metastasis is the leading cause of death in cancer patients. However, it is unclear whether lycopene can act as an adjuvant to increase the anti-metastatic activity of anticancer drugs. Here, we examined the anti-lung-metastatic effects and the mechanism of lycopene in combination with sorafenib in C57BL/6 mice xenografted with Lewis lung carcinoma (LLC) cells. The mice were divided into five groups: (1) tumor control; (2) lycopene (5 mg/kg); (3) sorafenib (30 mg/kg); (4) lycopene (2 mg/kg) + sorafenib (30 mg/kg); (5) lycopene (5 mg/kg) + sorafenib (30 mg/kg). The results showed that lycopene reduced the number of metastatic tumors in the lungs, which was further suppressed by the combined treatment with sorafenib. The activities of matrix metalloproteinase (MMP)-2 and−9 were further inhibited and TIMP-1 and−2, and NM23-H1, the MMPs negative modulators, were further activated in the combined treatment. Mechanistically, we found that lycopene and sorafenib could additively inhibit the mitogen-activated protein kinase (MAPK) pathways, as shown by the protein phosphorylation of ERK1/2, JNK1/2 and p38 were reduced additively. Overall, the present study demonstrates that lycopene in combination with sorafenib additively inhibits the lung metastasis of tumor, indicating lycopene has potential as an adjuvant for sorafenib in cancer treatment.