Reduced Cancer Cell Viability Research Articles

Cannabidiol and Other Phytocannabinoids as Cancer Therapeutics.

Preclinical models provided ample evidence that cannabinoids are cytotoxic against cancer cells. Among the best studied phytocannabinoids, cannabidiol (CBD) is most promising for the treatment of cancer as it lacks the psychotomimetic properties of delta-9-tetrahydrocannabinol (THC). In vitro studies and animal experiments point to a concentration- (dose-)dependent anticancer effect. The effectiveness of pure compounds versus extracts is the subject of an ongoing debate. Actual results demonstrate that CBD-rich hemp extracts must be distinguished from THC-rich cannabis preparations. Whereas pure CBD was superior to CBD-rich extracts in most in vitro experiments, the opposite was observed for pure THC and THC-rich extracts, although exceptions were noted. The cytotoxic effects of CBD, THC and extracts seem to depend not only on the nature of cannabinoids and the presence of other phytochemicals but also largely on the nature of cell lines and test conditions. Neither CBD nor THC are universally efficacious in reducing cancer cell viability. The combination of pure cannabinoids may have advantages over single agents, although the optimal ratio seems to depend on the nature of cancer cells; the existence of a ‘one size fits all’ ratio is very unlikely. As cannabinoids interfere with the endocannabinoid system (ECS), a better understanding of the circadian rhythmicity of the ECS, particularly endocannabinoids and receptors, as well as of the rhythmicity of biological processes related to the growth of cancer cells, could enhance the efficacy of a therapy with cannabinoids by optimization of the timing of the administration, as has already been reported for some of the canonical chemotherapeutics. Theoretically, a CBD dose administered at noon could increase the peak of anandamide and therefore the effects triggered by this agent. Despite the abundance of preclinical articles published over the last 2 decades, well-designed controlled clinical trials on CBD in cancer are still missing. The number of observations in cancer patients, paired with the anticancer activity repeatedly reported in preclinical in vitro and in vivo studies warrants serious scientific exploration moving forward.

Withalutin, a new cytotoxic withanolide from Athenaea velutina (Sendtn.) D’Arcy

Bioassay-guided fractionation of dichloromethane extract from Athenaea velutina leaves led to the isolation of three withanolides, all being reported for the first time in this species. They were identified as withacnistin (1), withacnistin acetate (2) and a new withanolide, designated as withalutin (3). The structures were established by spectral data analysis, including MS, 1D and 2D NMR. In addition, in silico ADMET studies were employed to understand the pharmacokinetic properties of these withanolides. The withanolides isolated from A. velutina reduced cancer cell viability with IC50 values ranging from 1.52 to 5.39 µM. In silico prediction revealed that withanolides have good gastrointestinal absorption or oral bioavailability properties; and are not likely to be mutagenic or hepatotoxic. These findings revealed that A. velutina is an important source of cytotoxic withanolides.

Efficacy of MDX-124, a novel anti-annexin-A1 antibody, in preclinical models of pancreatic cancer.

590 Background: Pancreatic cancer is a highly fatal disease with poor survival and response to both chemotherapy and immunotherapy. Novel approaches to treat this disease are urgently required. Annexin-A1 (ANXA1) is secreted in response to several physiological stimuli where it activates formyl peptide receptors (FPR1/2) triggering multiple oncogenic processes. High ANXA1 expression in pancreatic cancer patients is associated with poor overall survival, and influences cancer progression, drug sensitivity, migration and invasion. MDX-124 is a novel humanized antibody targeting ANXA1 and we have previously presented data demonstrating its significant antiproliferative activity. Here we present further data showing the efficacy of MDX-124 in several preclinical models of pancreatic cancer. Methods: In-vitro models utilized MIA PaCa-2, PANC-1 or BxPC-3 human pancreatic cancer cell lines. Cell cycle progression was evaluated by measuring changes in DNA content via flow cytometry. Pancreatic cancer cell viability following incubation with MDX-124 (0-10 µM) and 5FU (IC50) was assessed via MTT assay. A transwell migration assay was used to evaluate the effect of MDX-124 (0-50 µM) on pancreatic cancer cell migration. In-vivo efficacy was evaluated using an orthotopic mouse model of metastatic pancreatic cancer (FC1242luc/zsGreen; KPC-derived cell line) with bioluminescent imaging used to quantify the incidence and burden of lung metastases. Results: When compared to untreated MIA PaCa-2 pancreatic cancer cells, MDX-124 treatment decreased the proportion of cells in S-phase by 29% and G2 phase by 9.1%, with a concomitant increase in G1 of 38.1%. This occurred in a dose-dependent manner and is consistent with an MDX-124 mediated increase in cell cycle arrest. MDX-124 significantly reduced the viability of MIA PaCa-2 and PANC-1 cell lines versus an IgG control in a dose-dependent manner. Additionally in these two cell lines, combination of MDX-124 with 5FU (IC50) had a significant synergistic impact reducing cancer cell viability by 99.8% and 91.2% respectively. Furthermore, MDX-124 significantly reduced the migratory ability of MIA PaCa-2 and BxPC-3 pancreatic cancer cells. In the orthotopic model of metastatic pancreatic cancer, the murine analog of MDX-124 (MDX-001), markedly reduced both the incidence and size of lung metastases. Conclusions: MDX-124 demonstrated significant anti-tumor efficacy in several preclinical models of pancreatic cancer as a single agent, with increased potency observed when used in combination with 5FU. Medannex will initiate a First-In-Human study in Q4 2021 to evaluate MDX-124 in solid malignancies, including pancreatic cancer.

Closed‐Loop Temperature‐Controlled Magnetic Hyperthermia Therapy with Magnetic Guidance of Superparamagnetic Iron‐Oxide Nanoparticles

AbstractHyperthermia therapy eliminates cancer cells by heating them above physiological temperatures. Superparamagnetic iron oxide nanoparticles (SPIONs) are promising for targeted hyperthermia therapy because of their excellent heating efficiency, biocompatibility, and active magnetic navigation. When exposed to a high‐frequency alternating magnetic field (AMF), SPIONs dissipate heat to damage cancer cells. Accurate temperature control is crucial for safe and efficient hyperthermia therapy. A closed‐loop temperature controller to control the temperature and heating rate by adjusting AMF’s strength, thereby enabling controllable hyperthermia therapy. Under a low‐frequency rotating magnetic field (RMF), the SPIONs form chains which can be actively manipulated towards the target by adjusting RMF’s direction, followed by AMF exposure for hyperthermia therapy. The SPIONs are precisely manipulated in a microfluidic chip and rat brain vessels ex vivo, highlighting the potential for targeted position control. Last, in vitro, and in vivo hyperthermia treatments are performed on human prostate cancer cells (PC3) and a PC3 xenograft mouse model using the proposed temperature controller, with tracking errors under 0.5°C and significant reduction in cancer cell viability and tumor volume. The magnetic locomotion with RMF, and the controlled heating using AMF, show the feasibility of using SPIONs for targeted hyperthermia therapy.

Effect of S14161 Small Molecule and Glaucium Flavum Extract on A549 Cancer Cells

Background: Lung cancer is the fifth most common cancer in Iran. Due to the side effects of common cancer treatments, everyone has turned to herbal remedies and new treatments. This study aimed to compare the effect of S14161 small molecule and Glaucium flavum extract on the induction of apoptosis in A549 cancer cells. Materials and Methods: In this experimental study, the A549 cell line was treated with different concentrations of G. flavum and S14161 on days 1, 3, and 5. Also, half maximal inhibitory concentrations (IC 50) for both G. flavum and S14161 were measured. In addition, the quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to investigate the effects of S14161 and G. flavum extract on the expressions level of Bax, Bad, P53, and Bcl2 genes. Results: Results showed that both the combination of S14161 and G. flavum extract resulted in cell death and reduced cancer cell viability. Nevertheless, the viability rate was greater by S14161, and this small molecule significantly increased the expression of Bax, P53, and Bad apoptotic genes and decreased the expression of the Bcl2 gene, which shows the induced apoptotic death and lethal effect of S14161 in comparison with G. flavum extract. Conclusion: Our study showed that S14161 had fewer IC50 and caused cell death by inhibiting the PI3K/AKT pathway, and G. flavum caused cancer cell death due to its alkaloid compounds. Therefore, both compounds are recommended as drug candidates for the treatment of lung cancer.

Comparison of the Effect of S14161 Small Molecule and Glaucium Flavum Extract on A549 Cancer Cells

Background: Lung cancer is the fifth most common cancer in Iran. Due to the side effects of common cancer treatments, everyone has turned to herbal remedies and new treatments. This study aimed to compare the effect of S14161 small molecule and Glaucium flavum extract on the induction of apoptosis in A549 cancer cells. Materials and Methods: In this study, the A549 cell line was treated with different concentrations of S14161 small molecule and G. flavum extract compounds. MTT assay was performed to determine the half-maximal inhibitory concentration (IC50) and compare the viability of treated cells on days 1, 3, and 5. Also, the real-time polymerase chain reaction assay was used to investigate the expressions of pro- and anti-apoptotic genes. Results: MTT results showed that both the combination of S14161 and G. flavum extract resulted in cell death and reduced cancer cell viability. However, the viability rate was greater by S14161, and this small molecule significantly increased the expression of Bax, P53, and Bad apoptotic genes and decreased the expression of the Bcl2 gene, which shows the induced apoptotic effect of S14161 in comparison with G. flavum. Conclusion: The results of this study showed that S14161 had fewer IC50 and caused cell death by inhibiting the PI3K/AKT pathway, and Glaucium flavum caused cancer cell death due to its alkaloid compounds. Therefore, both compounds are recommended as drug candidates for the treatment of lung cancer.[GMJ.2021;10:e2151]

Assessing the antiumer and anti-inflammatory potentials of Calotropis procera latex

Since time immemorial medicinal plants have been used in healthcare to treat different human disease. The ideals of medicinal plants are highlighted due to the utility of the common-factor approach to engage other health promoters in propagating. One of these medicinal plants is Calotropis procera which is a species of tree in the family Apocynaceae. Calotropis procera is widespread in tropical Africa, including the Indian Ocean islands and the northern parts of South Africa. The latex is toxic and can cause rash, blisters and serious inflammations in sensitive persons and it may lead to blindness. Several side effects may be caused due to ingestion large doses of latex like burning in the throat, irritation of the stomach, nausea, vomiting, diarrhea, tremors, vertigo and convulsions. This study aimed to evaluate burns healing effects and inhibitory concentration IC50 of Calotropis procera latex on cervical cancer cell line, SiHa. Cytotoxicity analysis was performed by MTT assay in addition to determine the burns healing effect of the latex by determining the day requiring to heal the burn skin of albino male mice. The results of burns healing effects declared that the burns required 12 days to heal in comparison with positive (sliver sulfadiazine) and negative control which required 16 and 18 days for healing respectively. Also, the results revealed that the IC50 of latex was 146.8 % in comparison of ambiguous percentage of normal cell line WRL68 with reduction in cancer cell viability ranging from 95.87± 0.20to 52.35 ±3.31 for 6.2 to 400 µg\ml respectively.

Mass transfer of anti‐cancer drug delivery to brain tumors by a multiple emulsion‐based implant

AbstractThe advanced use of a pH‐responsive biomaterial‐based injectable liquid implant for effective chemotherapeutic delivery in glioblastoma multiforme (GBM) brain tumor treatment is presented. As an implant, we proposed a water‐in‐oil‐in‐water multiple emulsion with encapsulated doxorubicin. The effectiveness of the proposed therapy was evaluated by comparing the cancer cell viability achieved in classical therapy (chemotherapeutic solution). The experimental study included doxorubicin release rates and consumption for two emulsions differing in drop sizes and structures in the presence of GBM‐cells (LN229, U87 MG), and a cell viability. The results showed that the multiple emulsion implant was significantly more effective than classical therapy when considering the reduction in cancer cell viability: 85% for the emulsion‐implant, and only 43% for the classical therapy. A diffusion–reaction model was adapted to predict doxorubicin release kinetics and elimination by glioblastoma cells. CFD (computational fluid dynamics) simulations confirmed that the drug release kinetics depends on multiple emulsion structures and drop sizes.

Evaluation of Anticancer Effects and Molecular Mechanisms of Pomegranate Peel Extract in the Mouse Cellular Model (4T1) of Breast Cancer

Background: Breast cancer is the most common female cancer that, despite recent progress, its existing therapies do not have sufficient efficiency, and scientists are trying to find complementary therapies. Medicinal plants, such as pomegranate (Punica granatum L.), attract a great deal of attention in this regard. Objectives: The present study aimed to assess the anticancer effects of pomegranate peel alcoholic extract (PPE) in the mouse cellular model (4T1) of breast cancer and investigate the related molecular mechanism of antiproliferative effects of the extract through the evaluation of the expression level of apoptosis genes (ie, BAX and BCL2). Methods: For the accomplishment of the study objectives, after the preparation of PPE, an evaluation of cellular cytotoxicity was carried out using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. According to the MTT assay, the cells were treated for 24 h with selective doses of the extract. Then, ribonucleic acid extraction, complementary deoxyribonucleic acid synthesis, and gene expression analysis of BAX and BCL2 using real-time polymerase chain reaction were performed in this study. Results: The results showed that PPE reduced cancer cell viability in a dose- and time-dependent manner. The molecular analysis indicated that observed cell death could be due to an increase in the BAX/BCL2 ratio. Conclusions: Overall, PPE can be proposed as a potential complementary therapy for breast cancer. However, further studies on animal models and clinical trials are needed to verify the clinical usage of such complementary drugs.

Biological Potential of Silver Nanoparticles Mediated by Leucophyllum frutescens and Russelia equisetiformis Extracts.

Awareness about environmental concerns is increasing, specially the pollution resulting from nanoparticles (NPs) production, which has led to great interest in the usage of biogenic agents for their fabrication. The current investigation used eco-friendly organic phytomolecules from Leucophyllum frutescens and Russelia equisetiformis leaves extract for the first time in the fabrication of silver NPs from silver ions and further an assessment of their biological activities was performed. The leaves extract from both plant sources were used as capping and reducing agents and added to AgNO3. The mixtures were observed for colour changes, and after a stable dark brown colour was obtained, the NPs were separated and further investigated using dynamic light scattering, transmission electron microscopy and energy-dispersive X-ray spectroscopy. The Fourier transform infrared spectroscopy technique was employed to determine the active organic ingredients in the plant extracts. The prepared NPs were tested against three cell lines (two cancer ones and one normal control) and the effects observed using TEM and confocal laser scanning microscopy (LSM). Antibacterial activity against two Gram positive and two Gram negative species was examined and the synergistic effect of the ampicillin-NPs conjugate was studied. Findings showed successful conversion of Ag ions into L-AgNPs and R-AgNPs achieved using L. frutescens and R. equisetiformis extracts, respectively. A mean size of 112.9 nm for L-AgNPs and 151.7 nm for R-AgNPs and negative zeta potentials were noted. TEM analysis showed spherical NPs and EDS indicated Ag at 3 keV. Reduction in cancer cell viability with low half-maximal inhibitory concentrations was noted for both tested NPs. Structural changes and apoptotic features in the treated cancer cell lines were noted by TEM and cell death was confirmed by LSM. Furthermore, higher antibacterial activity was noticed against Gram positive compared with Gram negative bacteria as well as high synergistic effect was noted for the Amp-NPs conjugate, specially against Gram positive bacteria. The current investigation has thus developed an eco-friendly NPs synthesis route by applying plant extracts to efficiently produce NPs endowed with potential cytotoxic and antibacterial capacity, which therefore could be recommended as new approaches to overcome human diseases with minimal environmental impact.

Allium willeanum Holmboe exerts anticancer activities on metastatic breast cancer cells MCF-7 and MDA-MB-231

Allium species are medically important plants, rich in bioactive molecules with antitumoral properties. In this study, we aimed to investigate the molecular composition and in vitro anticancer activities of Allium willeanum Holmboe, an endemic Allium species of the island of Cyprus. GC-MS analysis of ethanolic extracts of A. willeanum H. bulb (AWB) showed bioactive molecules, octadecanoic acid 2-hydroxy-1-(hydroxymethyl)ethyl ester (21.99 %), hexadecanoic acid (20.42 %), pentadecanoic acid (9.19 %), 1,2-benzenedicarboxylic acid, diethyl ester (8.79 %), with known anticancer activities. AWB exerted significant reduction in mitochondria dependent metabolic activity as a measure of cell growth on MCF-7 (weakly metastatic) and MDA-MB-231 (strongly metastatic) human breast cancer (BCa) cell lines with a more prominent effect on highly metastatic BCa cells. Both trypan blue and lactate dehydrogenase (LDH) cytotoxicity assays quantitatively revealed that exposure to AWB extract significantly reduced cancer cell viability in both tested cell types. Differential activation of caspases in the tested cell lines indicated faster apoptotic activity on MDA-MB-231 cells compared to MCF-7. A significant reduction in cell motility was demonstrated upon AWB exposure of MCF-7 and MDA-MB-231 cells. AWB bioactive molecules collectively act on cancer cells to exert significant cytotoxic, apoptotic activities on both MCF-7 and MDA-MB-231 cells and significantly reduce their lateral motility, elucidating AWB as a promising agent to further be utilized in anticancer studies.

Design, Synthesis and Biological Evaluation of New 5‐(2‐Nitrophenyl)‐1‐aryl‐1H‐pyrazoles as Topoisomerase Inhibitors

Abstract5‐(2‐Nitrophenyl)‐1‐aryl‐1H‐pyrazoles are designed as topoisomerase (Topo) inhibitors, synthesised and assessed for their anticancer properties against breast (MDA‐MB‐231 and MCF7), lung (A549), and colorectal (HCT116) cancer cell lines. All the compounds induced significant cytotoxicity at low micromolar concentration. The compound 5e exerted potential anticancer effects on breast cancer cell lines at a low micromolar level (IC50<2 μM), and showed negligible toxicity towards normal cells. Compound 5 e reduced reactive oxygen species (ROS) level in breast cancer cells, altered mitochondrial membrane potential and induced the cell cycle arrest at the G2/M phase. This was accompanied by downregulation of oncogenic p‐Akt and upregulation of p‐PTEN along with modulation of apoptotic markers suggesting multiple mechanisms to reduce cancer cell viability. Finally, the topoisomerase inhibition assay revealed the inhibitory activity of 5 e against Topo I and Topo II.

Reengineering Tumor Microenvironment with Sequential Interleukin Delivery.

Some cytokines can reengineer anti-tumor immunity to modify the tumor micro-environment. Interleukin-27 (IL-27) can partially reduce tumor growth in several animal models, including prostate cancer. We hypothesized that addition of IL-18, which can induce the proliferation of several immune effector cells through inducing IFNγ could synergize with IL-27 to enhance tumor growth control. We describe our findings on the effects of IL-27 gene delivery on prostate cancer cells and how sequential therapy with IL-18 enhanced the efficacy of IL-27. The combination of IL-27 followed by IL-18 (27→18) successfully reduced cancer cell viability, with significant effects in cell culture and in an immunocompetent mouse model. We also examined a novel chimeric cytokine, comprising an IL-27 targeted at the C-terminus with a short peptide, LSLITRL (27pepL). This novel cytokine targets a receptor upregulated in tumor cells (IL-6Rα) via the pepL ligand. Interestingly, when we compared the 27→18 combination with the single 27pepL therapy, we observed a similar efficacy for both. This efficacy was further enhanced when 27pepL was sequenced with IL-18 (27pepL→18). The observed reduction in tumor growth and significantly enriched canonical pathways and upstream regulators, as well as specific immune effector signatures (as determined by bioinformatics analyses in the tumor microenvironment) supported the therapeutic design, whereby IL-27 or 27pepL can be more effective when delivered with IL-18. This cytokine sequencing approach allows flexible incorporation of both gene delivery and recombinant cytokines as tools to augment IL-27’s bioactivity and reengineer efficacy against prostate tumors and may prove applicable in other therapeutic settings.

A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer.

Simple SummaryThe dysregulation of UPS exacerbates the tumor microenvironment and drives malignant transformation. As the largest family of E3 ligases, the SCFF-boxes promotes BRCA progression. FBXL8 was recently identified to be a novel SCF E3 ligase that potently promotes BRCA. Here, we profiled the transcriptome of BRCA patient tissues by global NGS RNA-Seq and TCGA database analyses. A signature of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, CCNF) was found to be pivotal for BRCA advancement. Knockdown of FBXL8 and FBXO43 reduced cancer cell viability and proliferation, suggesting their pro-tumorigenic roles. However, the overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. FBXL8 and FZR1 pulled down CCNF, and double knockdown of FBXL8 and FZR1 caused CCNF accumulation. Additionally, CCNF partnered with a pro-tumorigenic factor, RRM2, and overexpression of CCNF reduced RRM2. Our findings suggest a potential for drugging CCNF in co-modulatory partnership with FBXL8 and FZR1, for anti-BRCA therapy.Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression.

Combined Inhibition of p38MAPK and PIKfyve Synergistically Disrupts Autophagy to Selectively Target Cancer Cells

In nutrient-poor conditions, autophagy buffers metabolic stress and counteracts the effects of chemotherapy and radiation on cancer cells, which depend on autophagy for survival. However, clinical trials targeting autophagy have failed to produce successful anticancer treatments using currently available inhibitors. Recent studies have shown that PIKfyve kinase inhibitors disrupt lysosome function in autophagy and can selectively kill certain cancer cells. Analysis of biochemical changes caused by PIKfyve inhibition revealed that resistant cells contain significantly higher levels of cellular p38MAPK protein and phosphorylation. Expression of the lysosomal protein, lysosomal-associated membrane protein 2, carrying phosphomimetic mutations of the p38MAPK phosphorylation sites prevented all effects caused by PIKfyve inhibition-induced lysosome dysfunction. Thus, the activation of p38MAPK in response to PIKfyve inhibition revealed a novel compensatory role in maintaining lysosome function in autophagy. The functional cooperation between the cellular PIKfyve and p38MAPK pathways in regulating lysosome homeostasis was especially important in cancer cells. Combined inhibition of PIKfyve and p38MAPK activities synergistically blocked autophagy-mediated protein degradation, prevented cathepsin maturation, and markedly reduced the viability of multiple cancer cell types without affecting the viability of normal cells. Furthermore, combined PIKfyve and p38MAPK inhibitors synergistically reduced tumor growth in mice bearing xenografts of human colorectal adenocarcinoma, suggesting a novel way to target cancer cells by prolonged inhibition of autophagy using lower drug concentrations. SIGNIFICANCE: This study demonstrates that PIKfyve and p38MAPK cooperate to regulate lysosome homeostasis and their combined inhibition synergistically blocks autophagy to reduce cancer cell viability in vitro and in vivo.

MicroRNA-214 enriched exosomes from human cerebral endothelial cells (hCEC) sensitize hepatocellular carcinoma to anti-cancer drugs.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor worldwide. Current medical therapy for HCC has limited efficacy. The present study tests the hypothesis that human cerebral endothelial cell-derived exosomes carrying elevated miR-214 (hCEC-Exo-214) can amplify the efficacy of anti-cancer drugs on HCC cells. Treatment of HepG2 and Hep3B cells with hCEC-Exo-214 in combination with anti-cancer agents, oxaliplatin or sorafenib, significantly reduced cancer cell viability and invasion compared with monotherapy with either drug. Additionally, the therapeutic effect of the combination therapy was detected in primary tumor cells derived from patients with HCC. The ability of hCEC-Exo-214 in sensitizing HCC cells to anti-cancer drugs was specific, in that combination therapy did not affect the viability and invasion of human liver epithelial cells and non-cancer primary cells. Furthermore, compared to monotherapy with oxaliplatin and sorafenib, hCEC-Exo-214 in combination with either drug substantially reduced protein levels of P-glycoprotein (P-gp) and splicing factor 3B subunit 3 (SF3B3) in HCC cells. P-gp and SF3B3 are among miR-214 target genes and are known to mediate drug resistance and cancer cell proliferation, respectively. In conclusion, the present in vitro study provides evidence that hCEC-Exo-214 significantly enhances the anti-tumor efficacy of oxaliplatin and sorafenib on HCC cells.

Ultrasound Therapy, Chemotherapy and Their Combination for Prostate Cancer.

Prostate cancer is the second leading cause of cancer death in men. Its current treatment includes various physical and chemical approaches for the localized and advanced prostate cancer [e.g. metastatic castrate resistant prostate cancer (mCRPC)]. Although many new drugs are now available for prostate cancer, none is suitable for local treatment that can reduce adverse effects often associated with the current physical treatment. Of the drugs approved by FDA for mCRPC, the best mean improvement in overall survival is only about 4.8 months. Therefore, there is a need for improved treatment approaches for prostate cancer, especially drug-resistant cancer.Ultrasound therapy represents a useful new physical approach for the drug-resistant cancer treatment by facilitating the entry of the related chemotherapy drug into the target cancer cells. There are two versions of ultrasound: High Intensity Focused Ultrasound (HIFU) and Low Intensity Pulsed Ultrasound (LIPUS). HIFU has been a promising treatment option for prostate cancer due to its noninvasiveness and various biological effects on cancer tissue. It has been approved for the treatment of cancer and in recent years there have been numerous findings suggesting HIFU can reduce cancer cell viability and possibly reverse the spread of cancerous tumors. LIPUS is currently being studied as an alternative treatment option for prostate cancer. Preliminary studies have found LIPUS to reduce cancer cell viability without the side effects seen in HIFU. Reversible cell membrane damage caused by LIPUS could allow increased uptake of anticancer drugs, enhancing cytotoxicity and death of cancer cells. In this way, a low dose of anticancer drug is more effective toward cancer cells while there is less damage to normal cells. The combination of LIPUS with certain chemotherapeutic agents can be an exciting physical-chemical combination therapy for prostate cancer. This review will focus on this topic as well as the clinical use of HIFU to provide an understanding of their current use and future potential role for prostate cancer therapy.

Fancy-Shaped Gold-Platinum Nanocauliflowers for Improved Proton Irradiation Effect on Colon Cancer Cells.

Enhancing the effectiveness of colorectal cancer treatment is highly desirable. Radiation-based anticancer therapy—such as proton therapy (PT)—can be used to shrink tumors before subsequent surgical intervention; therefore, improving the effectiveness of this treatment is crucial. The addition of noble metal nanoparticles (NPs), acting as radiosensitizers, increases the PT therapeutic effect. Thus, in this paper, the effect of novel, gold–platinum nanocauliflowers (AuPt NCs) on PT efficiency is determined. For this purpose, crystalline, 66-nm fancy shaped, bimetallic AuPt NCs were synthesized using green chemistry method. Then, physicochemical characterization of the obtained AuPt NCs by transmission electron microscopy (TEM), selected area electron diffraction (SAED), energy dispersive X-ray spectroscopy (EDS), and UV-Vis spectra measurements was carried out. Fully characterized AuPt NCs were placed into a cell culture of colon cancer cell lines (HCT116, SW480, and SW620) and a normal colon cell line (FHC) and subsequently subjected to proton irradiation with a total dose of 15 Gy. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test, performed after 18-h incubation of the irradiated cell culture with AuPt NCs, showed a significant reduction in cancer cell viability compared to normal cells. Thus, the radio-enhancing features of AuPt NCs indicate their potential application for the improvement in effectiveness of anticancer proton therapy.

Doxorubicin-Conjugated Iron Oxide Nanoparticles Synthesized by Laser Pyrolysis: In Vitro Study on Human Breast Cancer Cells.

Even today, breast cancer remains a global public problem, with a high mortality rate among women. Nanoparticle (NP) based systems are developed to enhance drug delivery, reducing the toxic effect of medicine molecules. By using iron oxide nanoparticles for cancer treatment, several advantages were highlighted: the ability to target specific locations derived from their magnetic properties and reduced side effects. The aim of this study was to examine on breast cancer cell line the anticancer potential of γ-Fe2O3 NPs loaded with doxorubicin (DOX) and stabilized with carboxymethylcellulose sodium (CMCNa). The γ-Fe2O3 NPs were synthesized by laser pyrolysis technique and their nanometric size and crystallinity were confirmed by X-ray diffraction and transmission electron microscopy. The loading efficiency was estimated by using absorption and fluorescence spectroscopy. The DOX conjugated//CMCNa coated γ-Fe2O3 NPs proved through the biological studies to have a good anticancer effect through the inhibition of tumoral cell proliferation, disruption of the cellular membrane, induction of cell death and reduced effects on normal breast cells. Our data showed that DOX cytotoxicity increases significantly when conjugated with ɣ-Fe2O3 and ɣ-Fe2O3_CMCNa, a 50% reduction of cancer cell viability was obtained with a concentration around 0.1 µg/mL.

Acoustically Mediated Controlled Drug Release and Targeted Therapy with Degradable 3D Porous Magnetic Microrobots.

Microrobots for targeted drug delivery are of great interest due to their minimal invasiveness and wireless controllability. Here, a magnetically driven porous degradable microrobot (PDM) is reported that consists of a 3D printed helical soft polymeric chassis made of a poly(ethylene glycol) diacrylate and pentaerythritol triacrylate matrix containing magnetite nanoparticles and the anticancer drug 5-fluorouracil (5-FU). The encapsulated Fe3 O4 nanoparticles render the PDM a precise wireless magnetic actuation by means of rotating magnetic fields (RMFs). The increased surface area of the porous PDM facilitates the acoustically induced drug release due to a higher response to the acoustic energy. The drug release profile from the PDM can be selected on command from three different modes, referred to herein as natural, burst, and constant, by differentiating the ultrasound exposure condition. Finally, in vitro test results reveal different therapeutic results for each release mode. The observed great reduction of cancer cell viability in the burst- and constant-release modes confirms that ultrasound with the proposed PDM can enhance the therapeutic effect by increasing drug concentration and sonoporation.