Blueberry extract and its bioactive compounds mitigate oxidative stress and suppress human lung cancer cell (A549) growth by modulating the expression of p53/EGFR/STAT3/IL6-mediated signaling molecules.

Bioactive phytocompounds are crucial components in all plants. Since the time of traditional medicine, the utilization of plants has been grounded in the potential of these bioactive compounds to treat or manage specific illnesses. These natural bioactive compounds have sparked growing interest in employing medicinal plants for addressing various conditions, such as inflammatory diseases, diabetes, and cancer. This study focuses on assessing the qualitative phytochemical composition, antioxidant potential, and cytotoxic effects of blueberry (Vaccinium sect. Cyanococcus) extract using three different solvents, namely water, ethanol, and methanol. The extract exhibited notable antioxidant activities, as evidenced by DPPH and H2O2 free radical scavenging assays. The cell viability assay also demonstrated cell growth inhibition in A549 cells. Furthermore, nine specific phytocompounds sourced from existing literature were selected for molecular docking studies against CDK6 and, AMPK key protein kinases which enhance the cancer progression. The molecular docking results also revealed favorable binding scores, with a high score of -9.5 kcal/mol in CDK6 protein and a maximum score of AMPK with targets of -8.8 kcal/mol. The selected phytocompounds' pharmacodynamic properties such as ADMET also supported the study. Furthermore, rutin stated that pre-dominantly present in blueberry plants shows a potent cytotoxicity effect in A549 cells. Functional annotations by bioinformatic analysis for rutin also revealed the strong enrichment in the involvement of PI3K/AKT1/STAT, and p53 signaling pathways. Based on this analysis, the identified rutin and other compounds hold a promising anticancer activity. Overall, the comprehensive evaluation of both in vitro and in silico data suggests that the Vaccinium sect. Cyanococcus extract could serve as a valuable source of pharmaceutical agents and may prove effective in future therapeutic applications.

Farm or Lab? A Comparative Study of Oregano's Leaf and Callus Volatile Isolates Chemistry and Cytotoxicity.

Oregano (Origanum vulgare, Lamiaceae plant family) is a well-known aromatic herb with great commercial value, thoroughly utilized by food and pharmaceutical industries. The present work regards the comparative assessment of in vitro propagated and commercially available oregano tissue natural products. This study includes their secondary metabolites' biosynthesis, antioxidant properties, and anticancer activities. The optimization of callus induction from derived oregano leaf explants and excessive oxidative browning was performed using various plant growth regulators, light conditions, and antioxidant compounds. The determination of oregano callus volatiles against the respective molecules in maternal herbal material was performed using gas chromatography-mass spectrometry (GC/MS) analysis. In total, the presence of twenty-seven phytochemicals was revealed in both leaf and callus extracts, from which thirteen molecules were biosynthesized in both tissues studied, seven compounds were present only in callus extracts, and seven metabolites only in leaf extracts. Carvacrol and sabinene hydrate were the prevailing volatiles in all tissues exploited, along with alkanes octacosane and triacontane and the trimethylsilyl (TMS) derivative of carvacrol that were detected in significant amounts only in callus extracts. The MTT assay was employed to assess the in vitro cytotoxic properties of oregano extracts against the epithelial human breast cancer MDA-MB-231 and the human neuroblastoma SK-N-SH cell lines. The extracts displayed concentration and time-dependent responses in cell proliferation rates.

Effect of a Low-Level Laser on Liposomal Doxorubicin Efficacy in a Melanoma Cell Line.

Introduction: The cytotoxicity of chemotherapy drugs is a significant challenge in the way of surmounting cancer. Liposomal drug delivery has proven to be efficacious in increasing the function of the drugs. Its potential to accumulate drugs in the target site and enhance the efficiency of anti-cancer agents with lower doses hinders their cytotoxicity on normal healthy cells. Since the release of drugs from liposomes is not generally on a controlled basis, several studies have suggested that external stimuli including lasers could be used to induce controlled release and boost the efficiency of liposomal drug delivery systems (LDDSs). Methods: The A375 cancer cell line was used and exposed to the liposomes containing doxorubicin in the presence of a low-level laser beam to investigate its effect on the liposomal stimuli-responsiveness release and its toxicity on cancer cells. So as to achieve that goal, Annexin V/PI was employed to analyze the number of cells that underwent apoptosis and necrosis. Results: Here, we report the effect of laser irradiation on LDDSs. According to the results obtained from the annexin V/PI assay, the pattern of viability status has shifted, so that the number of pre-apoptotic cells treated with liposomal doxorubicin and a laser beam was more than that of cells treated with only liposomal doxorubicin. Conclusion: The use of stimuli-responsive LDDSs, in this case, laser-responsive, has led to favorable circumstances in the treatment of cancer, offering enhanced cancer cell cytotoxicity.

Improving Cytotoxicity against Breast Cancer Cells by Using Mixed-Ligand Ruthenium(II) Complexes of 2,2'-Bipyridine, Amino Acid, and Nitric Oxide Derivatives as Potential Anticancer Agents.

BACKGROUND: Several metal-based molecules that display cytotoxicity against multiple cell lines have been pursued in an attempt to fight against cancer and to overcome the typical side effects of drugs like cisplatin. In this scenario, ruthenium complexes have been extensively studied due to their activity in both in vitro and in vivo biological systems, including various cancer cell strains. OBJECTIVE: We aimed to develop a method to synthesize novel [Ru(NO)(bpy)2L2]2+ complexes containing amino acid ligands by using an alternative Click Chemistry approach, namely the copper azide-alkyne cycloaddition reaction (CuAAC reaction), to construct nitrosyl/nitrite complexes bearing a modified lysine residue. METHODS: We synthesized a new ligand by Click Chemistry approach and new compounds bearing the unprecedented ligand. Cytotoxicity was assessed by the classical MTT colorimetric assay. MCF-7 and MDAMB- 231 cells were used as breast cancer cell models. MCF-10 was used as a model of healthy cells. RESULTS: Amino acid ligands related to N3-Lys(Fmoc) and the new pyLys were successfully synthesized by the diazotransfer reaction and the CuAAC reaction, respectively. The latter reaction involves coupling between N3-Lys(Fmoc) and 3ethynylpyridine. Both N3-Lys(Fmoc) and the new pyLys were introduced into the ruthenium bipyridine complex I, or cis-[RuII(NO)(NO2)(bpy)2]2+, to generate the common nitro-based complex III, which was further converted to the final complex IV. Results of the MTT assay proved the cytotoxic effect of cis- [RuII(NO)(pyLysO-)(bpy)2](PF6)2 against the mammalian breast cancer cells MCF-7 and MDA-MB231. CONCLUSION: The viability assays revealed that complex IV, bearing a NO group and a modified lysine residue, was able to release NO and cross tumor cell membranes. In this work, Complex IV was observed to be the most active ruthenium bipyridine complex against the mammalian breast cancer cells MCF-7 and MDA-MB231: it was approximately twice as active as cisplatin, whilst complexes I-III proved to be less cytotoxic than complex IV. Additional tests using healthy MCF 10A cells showed that complexes II-IV were three- to sixfold less toxic than cisplatin, which suggested that complex IV was selective against cancer cells.

Tributyltin(IV) ferulate, a novel synthetic ferulic acid derivative, induces autophagic cell death in colon cancer cells: From chemical synthesis to biochemical effects.

Ferulic acid (FA) is a natural phenolic phytochemical that has low toxicity and exhibits therapeutic effects against various diseases, behaving as an antioxidant. FA also displays modest antitumor properties that have been reported at relatively high concentrations. With the aim of improving the anti-tumor efficacy of FA, we synthesized the novel compound tributyltin(IV) ferulate (TBT-F). The coordination environment at the tin center was investigated spectroscopically. Following synthesis, chemical characterization and computational analysis, we evaluated TBT-F effects in colon cancer cells. The results showed that TBT-F, at nanomolar range concentrations, was capable of reducing the viability of HCT116, HT-29 and Caco-2 colon cancer cells. On the other hand, FA was completely inefficacious at the same treatment conditions. Cell viability reduction induced by TBT-F was associated with G2/M cell cycle arrest, increase in membrane permeabilization and appearance of typical morphological signs. TBT-F-induced cell death seemed not to involve apoptotic or necroptotic markers whereas autophagic vacuoles appearance and increase in LC3-II and p62 autophagic proteins were observed after treatment with the compound. The autophagy inhibitor bafylomicin A1 markedly prevented the effect of TBT-F on colon cancer cells, thus indicating that autophagy is triggered as a cell death process. Taken together, our results strongly suggest that the novel ferulic derivative TBT-F is a promising therapeutic agent for colon cancer since it is capable of triggering autophagic (type-II) cell death that may be important in case of resistance to classic apoptosis.

7-Chloroquinoline-1,2,3-triazoyl carboxamides induce cell cycle arrest and apoptosis in human bladder carcinoma cells.

In the present study, the antitumoral properties of a series of 7-chloroquinoline-1,2,3-triazoyl-carboxamides (QTCA) were investigated by analyzing their cytotoxic activities against human bladder cells (5637; grade II carcinoma). In addition, their effects on cell viability, cell cycle arrest mechanisms, apoptosis induction, in silico molecular docking, and detection of pro-apoptotic and anti-apoptotic proteins were evaluated. The cytotoxicity assay identified major dose- and time-dependent cytotoxic effects in 5637 cells after they were exposed to treatment with QTCA, only minimal effects were observed on normal cells. A live/dead assay confirmed that significant cell death, arrest in the G0/G1 phase and apoptosis were associated with treatment by 1-(7-Chloroquinolin-4-yl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (QTCA-1) and 1-(7-Chloroquinolin-4-yl)-N-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (QTCA-4). The in silico results indicated that these compounds acted through different mechanisms for the induction of cell cycle arrest and apoptosis. Western blotting confirmed the binding of the QTCAs to pro- and anti-apoptotic proteins. In conclusion, QTCA-1 and QTCA-4 are promising candidates for inducing cytotoxicity, cell cycle arrest, and apoptosis in human bladder cancer cells.

Novel Fluorine Boron Hybrid Complex as Potential Antiproliferative Drugs on Colorectal Cancer Cell Line.

OBJECTIVE: Colorectal Cancer (CRC) is one of the most common types of cancer in both sexes; it is considered to be the third leading death factor among other types of cancer. This study aimed to examine the cytotoxicity of a new fluorine boron hybrid complex [L(BF2)2] on human colorectal adenocarcinoma cell line (HT-29), based on the potency of the half-metal based complexes to initiate apoptosis. METHODS: Based on this data, the impact of it in different concentrations on HT-29 cancerous cells was determined by apoptosis (ELISA, DNA fragmentation laddering, AO/EB staining), cytotoxicity (MTT) and genotoxicity (comet assay). We also calculated the cellular Oxidative Stress Index (OSI) by measuring the Total Antioxidant Status (TAS) and Total Oxidant Status (TOS). RESULTS: Firstly, [L(BF2)2] was examined in view of cytotoxic effect in seven various cell lines (HELA, DU-145, PC3, DLD-1, ECC, PNT1-A and HT-29), and then it was found that the applied complex had a mighty antiproliferative action on HT-29 cells. Thus, the most effective IC50 value turned out to be 26.49 µM in HT-29 cell line. The present study found a tremendous efficacy of [L(BF2)2] on HT-29 cells, especially in terms of damage to cancer cells' DNA, and consequently caused a series of reactions leading to programmed cell death. CONCLUSION: The results suggest that the [L(BF2)2] as a novel fluorine boron hybrid complex can induce the apoptosis of HT-29 colorectal cancerous cell line and is a possible candidate for future cancer studies.

Cytotoxic profiling of artesunic and betulinic acids and their synthetic hybrid compound on neurons and gliomas.

Gliomas are brain-born tumors with devastating impact on their brain microenvironment. Novel approaches employ multiple combinations of chemical compounds in synthetic hybrid molecules to target malignant tumors. Here, we report on the chemical hybridization approach exemplified by artesunic acid (ARTA) and naturally occurring triterpene betulinic acid (BETA). Artemisinin derived semisynthetic compound artesunic acid (ARTA) and naturally occurring triterpene BETA were used to synthetically couple to the hybrid compound termed 212A. We investigated the impact of 212A and its parent compounds on glioma cells, astrocytes and neurons. ARTA and BETA showed cytotoxic effects on glioma cells at micromolar concentrations. ARTA was more effective on rodent glioma cells compared to BETA, whereas BETA exhibited higher toxic effects on human glioma cells compared to ARTA. We investigated these compounds on non-transformed glial cells and neurons as well. Noteworthy, ARTA showed almost no toxic effects on astrocytes and neurons, whereas BETA as well as 212A displayed neurotoxicity at higher concentrations. Hence we compared the efficacy of the hybrid 212A with the combinational treatment of its parent compounds ARTA and BETA. The hybrid 212A was efficient in killing glioma cells compared to single compound treatment strategies. Moreover, ARTA and the hybrid 212A displayed a significant cytotoxic impact on glioma cell migration. Taken together, these results demonstrate that both plant derived compounds ARTA and BETA operate gliomatoxic with minor neurotoxic side effects. Altogether, our proof-of-principle study demonstrates that the chemical hybrid synthesis is a valid approach for generating efficacious anti-cancer drugs out of virtually any given structure. Thus, synthetic hybrid therapeutics emerge as an innovative field for new chemotherapeutic developments with low neurotoxic profile.

Apoptosis induction by 7-chloroquinoline-1,2,3-triazoyl carboxamides in triple negative breast cancer cells.

Breast cancer is a major public health burden in both developed and developing countries and there is still a need to screen new molecules with different modes of actions. The aims of this study were to evaluate the selectivity profile, apoptotic cell death and cell cycle arrest induced by 7-chloroquinoline-1,2,3-triazoyl carboxamides derivatives in hormonal-dependent and hormonal-independent breast cancer cells. Results showed significantly decreased MCF-7 and MDA-MB-231 cells viability in vitro in a dose dependent manner after treatment with 7-chloroquinoline derivatives QTCA-1, QTCA-2 and QTCA-3. QTCA-1 displayed the highest cytotoxic activity from all the tested compounds in MDA-MB-231 with IC50 values of 20.60, 20.42 and 19.91µM in 24, 48 and 72h of treatment respectively. Apoptosis induction was also significantly higher in the hormonal-independent breast cancer cells, with 80.4% of dead cells in MDA-MB-231 and only 16.8% of dead in MCF-7 cells. As a result, G0/G1 cycle arrest was observed in MCF-7 cells and no cell cycle arrest at all was observed in MDA-MB-231 cells. Molecular docking showed a high affinity of QTCA-1 to PARP-1, Scr and PI3K/mTOR targets. These results suggest a strong activity of the 7-chloroquinoline derivative QTCA-1 in independent-hormonal cells and suggest selectivity for triple negative cells.

Novel nanoemulsion based lipid nanosystems for favorable in vitro and in vivo characteristics of curcumin.

The goal of this study was to assess the enhanced elementary characteristics, in vitro release, anti-cancer cytotoxicity, in situ absorption and in vivo bioavailability of a novel nanoemulsion based lipid nanosystems containing curcumin (CNELNs) when administered orally. The CNELNs were first fabricated by loading water-in-oil nanoemulsions into lipid nanosystems using a nanoemulsion-film dispersion-sonication method. The gastro-intestinal absorption, in vitro release and in vivo kinetic property of CNELNs were investigated using an in situ perfusion method, a dialysis method and a concentration-time curve based method, respectively. The inhibitory effects of CNELNs on human lung cancer A549 cell growth were determined using MTT assay. The absorption constants and effective permeabilities of CNELNs in different gastro-intestinal tracts increased 2.29-4.04 times and 4.06-8.27 times that of curcumin (CUR), respectively. The relative bioavailability of CNELNs to free CUR was 733.59%. CNELNs inhibited A549 growth in a dose- and time-dependent manner. CNELNs markedly improved the oral bioavailability of CUR which was probably due to the increased gastro-intestinal absorption. CNELNs had stronger inhibitory effects on the viabilities of A549 cells than that of free CUR. CNELNs might be promising nanosystems for oral delivery of CUR to satisfy clinical requirements.