Comparison of vegetable oils on the uptake of lutein and zeaxanthin by ARPE-19 cells

AIM: To compare the effect of vegetable oils on the uptake of lutein and zeaxanthin by adult retinal pigment epithelial (ARPE)-19 cells in vitro. METHODS: ARPE-19 cells were cultured in Dulbecco's Modified Eagle Medium-F-12 supplemented with 10% foetal bovine serum and 1% penicillin–streptomycin in a humidified 5% CO2 incubator maintained at 37℃. Cells were treated with 247 µmol/L lutein, 49 µmol/L zeaxanthin and 1% (v/v) of either coconut oil, corn oil, peanut oil, olive oil, sunflower oil, soybean oil, castor oil, or linseed oil for 48h. Lutein and zeaxanthin concentration in the cells were quantified by high performance liquid chromatography. RESULTS: Among the oils tested, the highest lutein and zeaxanthin uptake was observed with coconut oil while the lowest was observed with linseed oil. CONCLUSION: ARPE-19 uptake of lutein and zeaxanthin are found to be dependent on the type of oils

Challenges and Opportunities of Nanotechnology as Delivery Platform for Tocotrienols in Cancer Therapy

Plant-derived phytonutrients have emerged as health enhancers. Tocotrienols from the vitamin E family gained high attention in recent years due to their multi-targeted biological properties, including lipid-lowering, neuroprotection, anti-inflammatory, antioxidant, and anticancer effects. Despite well-defined mechanism of action as an anti-cancer agent, their clinical use is hampered by poor pharmacokinetic profile and low oral bioavailability. Delivery systems based on nanotechnology were proven to be advantageous in elevating the delivery of tocotrienols to tumor sites for enhanced efficacy. To date, preclinical development of nanocarriers for tocotrienols include niosomes, lipid nanoemulsions, nanostructured lipid carriers (NLCs) and polymeric nanoparticles. Active targeting was explored via the use of transferrin as targeting ligand in niosomes. In vitro, nanocarriers were shown to enhance the anti-proliferative efficacy and cellular uptake of tocotrienols in cancer cells. In vivo, improved bioavailability of tocotrienols were reported with NLCs while marked tumor regression was observed with transferrin-targeted niosomes. In this review, the advantages and limitations of each nanocarriers were critically analyzed. Furthermore, a number of key challenges were identified including scale-up production, biological barriers, and toxicity profiles. To overcome these challenges, three research opportunities were highlighted based on rapid advancements in the field of nanomedicine. This review aims to provide a wholesome perspective for tocotrienol nanoformulations in cancer therapy directed toward effective clinical translation

The synthesis of trifluoromethylated N-nitroaryl-2-amino-1,3-dichloropropane derivatives and their evaluation as potential anti-cancer agents

Six N-nitroaryl-2-amino-1,3-dichloropropane derivatives have been prepared and evaluated against 18 cancer cell lines and two non-cancerous cell lines. Analysis of cell viability data and IC50 values indicated that the presence of a trifluoromethyl group in the nitroaryl moiety is an important structural feature associated with the compounds’ cytotoxicities

Zebularine and Trichostatin A sensitised human breast adenocarcinoma cells towards tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent due to its selective killing on cancer cells while sparing the normal cells. Nevertheless, breast adenocarcinoma cells can develop TRAIL resistance. Therefore, this project investigated the anti-cancer effects of the combination of epigenetic drugs zebularine and trichostatin A (ZT) with TRAIL (TZT) on the human breast adenocarcinoma cells. This treatment regimen was compared with the natural anti-cancer compound curcumin (Cur) and standard chemotherapeutic drug doxorubicin (Dox). As compared to TRAIL treatment, TZT treatment hampered the cell viability of human breast adenocarcinoma cells MDA-MB-231 significantly but not MCF-7 and immortalized non-cancerous human breast epithelial cells MCF10A. Unlike TZT, Cur and Dox treatments reduced cell viability in both human breast adenocarcinoma and epithelial cells significantly. Nevertheless, there were no changes in cell cycle in both TRAIL and TZT treatments in breast adenocarcinoma and normal epithelial cells. Intriguingly, Cur and Dox treatment generally induced G2/M arrest in MDA-MB-231, MCF-7 and MCF10A but Cur induced S phase arrest in MCF10A. The features of apoptosis such as morphological changes, apoptotic activity and the expression of cleaved poly (ADP) ribose polymerase (PARP) protein were more prominent in TRAIL and TZT-treated MDA-MB-231 as compared to MCF10A at 24 h post-treatment. Compared to TZT treatment, Cur and Dox treatments exhibited lesser apoptotic features in MDA-MB-231. Collectively, the sensitization using Zeb and TSA to augment TRAIL-induced apoptosis might be an alternative therapy towards human breast adenocarcinoma cells, without harming the normal human breast epithelial cells

Challenges and opportunities of nanotechnology as delivery platform for tocotrienols in cancer therapy

Plant-derived phytonutrients have emerged as health enhancers. Tocotrienols from the vitamin E family gained high attention in recent years due to their multi-targeted biological properties, including lipid-lowering, neuroprotection, anti-inflammatory, antioxidant and anticancer effects. Despite well-defined mechanism of action as an anti-cancer agent, their clinical use is hampered by poor pharmacokinetic profile and low oral bioavailability. Delivery systems based on nanotechnology were proven to be advantageous in elevating the delivery of tocotrienols to tumor sites for enhanced efficacy. To date, preclinical development of nanocarriers for tocotrienols include niosomes, lipid nanoemulsions, nanostructured lipid carriers (NLC) and polymeric nanoparticles. Active targeting was explored via the use of transferrin as targeting ligand in niosomes. In vitro, nanocarriers were shown to enhance the anti-proliferative efficacy and cellular uptake of tocotrienols in cancer cells. In vivo, improved bioavailability of tocotrienols were reported with NLCs while marked tumor regression was observed with transferrin-targeted niosomes. In this review, the advantages and limitations of each nanocarriers were critically analyzed. Furthermore, a number of key challenges were identified including scale-up production, biological barriers and toxicity profiles. To overcome these challenges, three research opportunities were highlighted based on rapid advancements in the field of nanomedicine. This review aims to provide a wholesome perspective for tocotrienol nanoformulations in cancer therapy directed towards effective clinical translation

Sphingosine kinase 1 regulates the survival of breast cancer stem cells and non-stem breast cancer cells by suppression of STAT1

Cancer stem cells (CSCs) represent rare tumour cell populations capable of self-renewal, differentiation and tumour initiation, and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches which can effectively target CSCs and tumour cells could be the key towards efficient tumour treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibits cell proliferation and induces apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhances breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signalling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrate that SPHK1 inhibitors, FTY720 and PF543 synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies

Co-culture systems for the production of secondary metabolites: current and future prospects

Microorganisms are the great sources of Natural Products (NPs); these are imperative to their survival apart from conferring competitiveness amongst each other within their environmental niches. Primary and secondary metabolites are the two major classes of NPs that help in cell development, where antimicrobial activity is closely linked with secondary metabolites. To capitalize on the effects of secondary metabolites, co-culture methods have been often used to develop an artificial microbial community that promotes the action of these metabolites. Different analytical techniques will subsequently be employed based on the metabolite specificity and sensitivity to further enhance the metabolite induction. Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography (GC)-MS are commonly used for metabolite separation while Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) have been used as tools to elucidate the structure of compounds. This review intends to discuss current systems in use for co-culture in addition to its advantages, with discourse into the investigation of specific techniques in use for the detailed study of secondary metabolites. Further advancements and focus on co-culture technologies are required to fully realize the massive potential in synthetic biological systems

Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization

Protein expression patterns in HEK-blue-cells treated with Clinacanthus nutans extracts

Background: Clinacanthus nutans (CN) is a small shrub native to tropical Asia known for their anti-oxidant, anti-inflammation, anti-cancer, and anti-viral activities. Objectives: This study aimed to investigate the effect of CN extract on human embryonic kidney cell line (HEK-Blue™-4) in a proteomic perspective. Materials and Methods: Comparative proteomic profiling through two-dimensional sodium dodecyl sulfate gel electrophoresis was performed on HEK-Blue™-4 treated with CN leaf polar extract. Results: We successfully identified seven upregulated proteins, of which five promoted the growth of the HEK-Blue™-4 cells. Interestingly, a potent antioxidant enzyme which neutralizes reactive oxygen or nitrogen species, peroxiredoxin-1 was also upregulated in HEK-Blue™-4 cell lines after treatment with CN leaf polar extract. Conclusion: CN leaf polar extract promotes the growth of HEK-Blue™-4 cells and induced the expression of peroxiredoxin-1, which protects the cells from reactive oxygen species during the inflammation process

Novel 2-benzoyl-6-(2,3- dimethoxybenzylidene)-cyclohexenol confers selectivity toward human MLH1 defective cancer cells through synthetic lethality

DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency