A new series of titanocene dichloride derivatives bearing cyclic alkylammonium groups: Assessment of their cytotoxic properties

Ten new water soluble titanocene dichloride derivatives have been synthesized and characterized and their cytotoxicities against the human lung cancer cell line A549 have been assessed. The potencies of the compounds vary greatly, but dicationic 3-picolylium and 4-picolylium compounds exhibit IC₅₀ values that are unusually low for this class of compounds. In view of their potency against A549 cells, three of the new complexes were tested further on additional human cell lines including the small cell lung cancer cell line H69, the widely used cervical carcinoma cell line HeLa, the ovarian carcinoma cell line A2780 and its cisplatin resistant derivative A2780/CP. All three compounds exhibited potencies in all cell lines comparable to or better than those observed with the A549 cells, while one complex is actually more potent than cisplatin for HeLa cells.     

Synthesis,characterization, and antitumor activity of novel tumor-targeted platinum(IV) complexes

Four tumor-targeted platinum(IV) complexes with ammonia and cyclohexylamine as the carrier groups and biotin as the axial group were designed, synthesized, and characterized. In vitro evaluation of the antitumor activity of complexes C1–C4 against lung cancer cells (A549), liver cancer cells (SMMC-7721), breast cancer cells (MCF-7), and colon cancer cells (SW480) was carried out. Complex C3 had the best cellular activity. Compared with cisplatin, complex C3 showed good anticancer activity against A549 cell line,complex C3 (6.34±0.44) is 3 times more cytotoxic than cisplatin (19.40±0.71),and against MCF-7 cell line complex C3 (4.22±0.11) is 5.4 times more cytotoxic than cisplatin (22.96±0.58), and against SW480 cell line complex C3 (6.65±0.60) is 3.4 times more cytotoxic than cisplatin (23.15±0.22). (Table 1) Axial chloride increased the redox power of complex C3 to increase the intercellular accumulation and the introduction of mixed amine had the ability to overcome cisplatin resistance. Complex C3 works best on MCF-7, then SW480, A549, and SMMC-7721. Thus, complex C3 is targeted by the axial introduction of biotin.     

The anti-lung cancer activity of propylene tethered dihydroartemisinin-isatin hybrids

Nineteen propylene tethered dihydroartemisinin-isatin hybrids 5a-g and 6a-l were designed, synthesized, and screened for their in vitro antiproliferative activity against three lung cancer cell lines, inclusive of drug-sensitive (A549), doxorubicin-resistant A549 (A549/DOX) and cisplatin-resistant A549 (A549/DDP) cell lines. The cytotoxicity of the synthesized hybrids towards normal lung epithelial cell line (BEAS-2B) was also assessed to evaluate the selectivity. The structure-activity relationship (SAR) elucidated that (1) alkyloxylimino fragment at C-3 position of isatin moiety were more favorable than the carbonyl and benzoxylimino, and the relative contricution order was methoxylimino > ethoxylimino > carbonyl > benzoxylimino; halogen atom at C-5 or C-6 position of isatin fragment could enhance the activity. Among them, hybrid 6f (IC₅₀: 21.7–28.9 μM) showed promising activity against the three tested lung cancer cell lines, and the activity was not inferior to that of cisplatin (IC₅₀: 19.7 and 66.9 μM) and doxorubicin (IC₅₀: 54.3 and 15.1 μM) against multidrug-resistant A549/DOX and A549/DDP lung cancer cell lines. In addition, hybrid 6f (IC₅₀: >100 μM) was non-cytotoxic towards normal lung epithelial cell line (BEAS-2B), and the RI values of hybrid 6f were 1.12 and 1.33. Further, hybrid 6f also possessed acceptable stability in mouse and human microsomes. Accordingly, hybrid 6a was a promising anti-lung cancer chemotherapeutic candidate and merited further evaluations.     

Anticancer β-hairpin peptides: membrane-induced folding triggers activity

Several cationic antimicrobial peptides (AMPs) have recently been shown to display anticancer activity via a mechanism that usually entails the disruption of cancer cell membranes. In this work, we designed an 18-residue anticancer peptide, SVS-1, whose mechanism of action is designed to take advantage of the aberrant lipid composition presented on the outer leaflet of cancer cell membranes, which makes the surface of these cells electronegative relative to the surface of noncancerous cells. SVS-1 is designed to remain unfolded and inactive in aqueous solution but to preferentially fold at the surface of cancer cells, adopting an amphiphilic β-hairpin structure capable of membrane disruption. Membrane-induced folding is driven by electrostatic interaction between the peptide and the negatively charged membrane surface of cancer cells. SVS-1 is active against a variety of cancer cell lines such as A549 (lung carcinoma), KB (epidermal carcinoma), MCF-7 (breast carcinoma), and MDA-MB-436 (breast carcinoma). However, the cytotoxicity toward noncancerous cells having typical membrane compositions, such as HUVEC and erythrocytes, is low. CD spectroscopy, appropriately designed peptide controls, cell-based studies, liposome leakage assays, and electron microscopy support the intended mechanism of action, which leads to preferential killing of cancerous cells.     

Benzofuran–isatin Hybrids: Design,Synthesis, and In Vitro Anti‐cancer Activities

A series of novel benzofuran–isatin hybrids 6a – s tethered through propylene and butylene were designed, synthesized, and evaluated for their in vitro anti‐cancer activities against HepG2 (liver carcinoma), Hela (cervical cancer), A549 (lung adenocarcinoma), DU145 (prostatic cancer), SKOV3 (ovarian carcinoma), MCF‐7 (breast cancer), and drug‐resistant MCF‐7/DOX (doxorubicin‐resistant MCF‐7) human cancer cell lines. The majority of the synthesized hybrids displayed weak to moderate in vitro activities against the tested seven cancer cell lines, but the enriched structure–activity relationship may pave the way for further optimization.     

Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells

Although lipids contribute to cancer drug resistance, it is challenging to target diverse range of lipids. Here, we show enzymatically inserting exceedingly simple synthetic lipids into membranes for increasing membrane tension and selectively inhibiting drug resistant cancer cells. The lipid, formed by conjugating dodecylamine to d -phosphotyrosine, self-assembles to form micelles. Enzymatic dephosphorylation of the micelles inserts the lipids into membranes and increases membrane tension. The micelles effectively inhibit a drug resistant glioblastoma cell (T98G) or a triple-negative breast cancer cell (HCC1937), without inducing acquired drug resistance. Moreover, the enzymatic reaction of the micelles promotes the accumulation of the lipids in the membranes of subcellular organelles (e.g., endoplasmic reticulum (ER), Golgi, and mitochondria), thus activating multiple regulated cell death pathways. This work, in which for the first time membrane tension is increased to inhibit cancer cells, illustrates a new and powerful supramolecular approach for antagonizing difficult drug targets.     

Cyclometalated Ruthenium(II) Anthraquinone Complexes Exhibit Strong Anticancer Activity in Hypoxic Tumor Cells

Hypoxia is the critical feature of the tumor microenvironment that is known to lead to resistance to many chemotherapeutic drugs. Six novel ruthenium(II) anthraquinone complexes were designed and synthesized; they exhibit similar or superior cytotoxicity compared to cisplatin in hypoxic HeLa, A549, and multidrug‐resistant (A549R) tumor cell lines. Their anticancer activities are related to their lipophilicity and cellular uptake; therefore, these physicochemical properties of the complexes can be changed by modifying the ligands to obtain better anticancer candidates. Complex 1 , the most potent member of the series, is highly active against hypoxic HeLa cancer cells (IC₅₀=0.53 μM ). This complex likely has 46‐fold better activity than cisplatin (IC₅₀=24.62 μM ) in HeLa cells. This complex tends to accumulate in the mitochondria and the nucleus of hypoxic HeLa cells. Further mechanistic studies show that complex 1 induced cell apoptosis during hypoxia through multiple pathways, including those of DNA damage, mitochondrial dysfunction, and the inhibition of DNA replication and HIF‐1α expression, making it an outstanding candidate for further in vivo studies.     

Let-7i miRNA and platinum loaded nano-graphene oxide platform for detection/reversion of drug resistance and synergetic chemical-photothermal inhibition of cancer cell

The drug resistance of chemotherapy is a major challenge to overcome for antineoplastic agents and the reverse of drug resistant is essential for cancer therapy. Herein, we developed a drug delivery system which can simultaneously detect/reverse the drug resistance and perform synergetic treatment of cancer. In this work, we integrated cyanine5(Cy5) modified mi RNA(let-7 i)(Cy5-mi RNA) and platinum onto nano-graphene oxide(NGO)(30-50 nm) platform to achieve simultaneously detection/reversion of ...     

Evaluation of the potential of Raman microspectroscopy for prediction of chemotherapeutic response to cisplatin in lung adenocarcinoma

The study of the interaction of anticancer drugs with mammalian cells in vitro is important to elucidate the mechanisms of action of the drug on its biological targets. In this context, Raman spectroscopy is a potential candidate for high throughput, non-invasive analysis. To explore this potential, the interaction of cis-diamminedichloroplatinum(II) (cisplatin) with a human lung adenocarcinoma cell line (A549) was investigated using Raman microspectroscopy. The results were correlated with parallel measurements from the MTT cytotoxicity assay, which yielded an IC(50) value of 1.2 ± 0.2 μM. To further confirm the spectral results, Raman spectra were also acquired from DNA extracted from A549 cells exposed to cisplatin and from unexposed controls. Partial least squares (PLS) multivariate regression and PLS Jackknifing were employed to highlight spectral regions which varied in a statistically significant manner with exposure to cisplatin and with the resultant changes in cellular physiology measured by the MTT assay. The results demonstrate the potential of the cellular Raman spectrum to non-invasively elucidate spectral changes that have their origin either in the biochemical interaction of external agents with the cell or its physiological response, allowing the prediction of the cellular response and the identification of the origin of the chemotherapeutic response at a molecular level in the cell.     

Synergistic Roles of Curcumin in Sensitising the Cisplatin Effect on a Cancer Stem Cell-Like Population Derived from Non-Small Cell Lung Cancer Cell Lines

Cancer stem cells (CSCs) represent a small subpopulation within a tumour. These cells possess stem cell-like properties but also initiate resistance to cytotoxic agents, which contributes to cancer relapse. Natural compounds such as curcumin that contain high amounts of polyphenols can have a chemosensitivity effect that sensitises CSCs to cytotoxic agents such as cisplatin. This study was designed to investigate the efficacy of curcumin as a chemo-sensitiser in CSCs subpopulation of non-small cell lung cancer (NSCLC) using the lung cancer adenocarcinoma human alveolar basal epithelial cells A549 and H2170. The ability of curcumin to sensitise lung CSCs to cisplatin was determined by evaluating stemness characteristics, including proliferation activity, colony formation, and spheroid formation of cells treated with curcumin alone, cisplatin alone, or the combination of both at 24, 48, and 72 h. The mRNA level of genes involved in stemness was analysed using quantitative real-time polymerase chain reaction. Liquid chromatography-mass spectrometry was used to evaluate the effect of curcumin on the CSC niche. A combined treatment of A549 subpopulations with curcumin reduced cellular proliferation activity at all time points. Curcumin significantly (p < 0.001) suppressed colonies formation by 50% and shrank the spheroids in CSC subpopulations, indicating inhibition of their self-renewal capability. This effect also was manifested by the down-regulation of SOX2, NANOG, and KLF4. Curcumin also regulated the niche of CSCs by inhibiting chemoresistance proteins, aldehyde dehydrogenase, metastasis, angiogenesis, and proliferation of cancer-related proteins. These results show the potential of using curcumin as a therapeutic approach for targeting CSC subpopulations in non-small cell lung cancer.     

An important role for peroxiredoxin II in survival of A549 lung cancer cells resistant to gefitinib

Redox adaptation is an important concept that explains the mechanisms by which cancer cells survive under persistent endogenous oxidative stress and become resistant to certain anticancer agents. To investigate this concept, we determined the expression levels of peroxiredoxins (Prxs), antioxidant enzymes in drug-resistant non-small cell lung carcinoma cells. Prx II was remarkably increased only in A549/GR (gefitinib-resistant) cells compared with A549 cells, consistent with methylation/demethylation. Prx II was highly methylated in the A549 cells but was demethylated in the A549/GR cells. The elevated expression of Prx II resulted in the downregulation of reactive oxygen species (ROS) and cell death and upregulation of cell cycle progression in the A549/GR cells. When Prx II mRNA in the A549/GR cells was knocked down, the levels of ROS and apoptosis were significantly recovered to the levels of the controls. In addition, signaling molecules involved in apoptosis were increased in the A549/GR-shPrx II cells. There was no difference in the expression of MAPK/ERK between the A549/GR cells and A549/GR-shPrx II cells, but the phosphorylation of JNK was increased in the A549/GR cells and was markedly decreased in the A549/GR-shPrx II cells. Colony number and tumor growth were significantly decreased in the A549/GR-shPrx II cells compared with the A549/GR cells. Our findings suggest that Prx II has an important role in cancer cell survival via the modulation of signaling molecules involved in apoptosis and the phosphorylation of JNK by the downregulation of ROS levels in A549/GR cells.     

Enzyme‐Instructed Intracellular Molecular Self‐Assembly to Boost Activity of Cisplatin against Drug‐Resistant Ovarian Cancer Cells

Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug‐resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme‐instructed self‐assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug‐resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre‐installed on the precursors to form the peptides that self‐assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug‐resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non‐cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.     

聚乙烯胺类修饰萘酰亚胺衍生物的合成、DNA键合行为和活性研究

合成了二乙烯三胺、三乙烯四胺和四乙烯五胺等低分子量聚乙烯胺类修饰的萘酰亚胺衍生物.通过UV-Vis谱、荧光光谱、圆二色谱和热变性试验研究了合成化合物与小牛胸腺DNA的键合行为,同时通过四甲基偶氮唑蓝(MTT)染色法研究了化合物对Bel-7402(人肝癌细胞)、HL-60(白血病细胞)、A549(人肺癌细胞)和Hela(人宫颈癌细胞)等细胞株的体外抗肿瘤活性,化合物NI1对A549细胞显示良好的抑制活性,优于阳性对照顺铂.     

Suppressed Migration and Enhanced Cisplatin Chemosensitivity in Human Cancer Cell Lines by Tuning the Molecular Mobility of Supramolecular Biomaterials

Cancer cells recognize physical cues transmitted from the surrounding microenvironment, and accordingly alter the migration and chemosensitivity. Cell adhesive biomaterials with tunable physical properties can contribute to the understanding of cancer cell responses, and development of new cancer therapies. Previously, it was reported that polyrotaxane-based surfaces with molecular mobility effectively modulate cellular functions via the yes-associated protein (YAP)-related signaling pathway. In the present study, the impact of molecular mobility of polyrotaxane surfaces on the migration and chemosensitivity of lung (A549), pancreatic (BxPC-3), and breast cancer (MDA-MB-231) cell lines is investigated, and it is found that the cellular spreading of adherent A549 and BxPC-3 cells and nuclear YAP translocation are promoted on low-mobility surfaces, suggesting that cancer cells alter their subcellular YAP localization in response to molecular mobility. Furthermore, low-mobility surfaces suppress cellular migration more than high-mobility surfaces. Additionally, low-mobility surfaces promote the cisplatin chemosensitivity of each cancer cell line to a greater extent than high-mobility surfaces. These results suggest that the molecular mobility of polyrotaxane surfaces suppresses cellular migration and enhances chemosensitivity via the subcellular translocation of YAP in cancer cells. Biointerfaces based on polyrotaxanes can thus be a new platform for elucidating cancer cell migration and chemoresistance mechanisms.     

Organometallic ruthenium and iridium phosphorus complexes: Synthesis,cellular imaging,organelle targeting and anticancer applications

The use of metal complexes containing phosphorus ligands as anticancer agents has not been well studied. In this work, eight novel half‐sandwich Ir^III and Ru^II compounds with P^P‐chelating ligands have been synthesized and fully characterized, and alongside two crystal structures were reported. All eight complexes displayed highly potent antiproliferative activity, up to nine times more potent than the clinical anticancer drug cisplatin towards A549 lung cancer cells. Complex Ir1 , which has a simpler structure and highly potent antiproliferative activity, was selected to investigate in further mechanistic studies. No hydrolysis and nucleobase binding occurred for complex Ir1 . In order to elucidate subcellular localization, the self‐luminescence of the complex Ir1 was utilized. Ir1 can specifically target lysosomes and facilitate excessive production of reactive oxygen species, resulting in lysosomal membrane permeabilization in A549 cells. Release of cathepsin B and changes in the mitochondria membrane potential also contributed to the observed cytotoxicity of Ir1 , which demonstrated an anticancer action mechanism that was different from that of cisplatin. The favorable results from biological and chemical research demonstrated that these types of complexes hold significant theranostic potential.     

Design,Synthesis, and In Vitro Anticancer Activities of Diethylene Glycol Tethered Isatin‐1,2,3‐triazole‐coumarin Hybrids

A series of novel diethylene glycol tethered isatin‐1,2,3‐triazole‐coumarin hybrids 9a – l were designed, synthesized, and evaluated for their in vitro anticancer activities against HepG2 (liver carcinoma), Hela (cervical cancer), A549 (lung adenocarcinoma), DU145 (prostatic cancer), SKOV3 (ovarian carcinoma), MCF‐7 (breast cancer), and drug‐resistant MCF‐7/DOX (doxorubicin‐resistant MCF‐7) human cancer cell lines. The results showed that most of the synthesized hybrids exhibited considerable in vitro activities against the tested seven cancer cell lines, and these hybrids can be acted as starting points for further investigation.     

Unique Use of Alkylation for Chemo‐Redox Activity by a PtIV Prodrug

Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin‐based therapy. A unique dual‐acting chemotherapeutic modality, Platin‐B, a prodrug of cisplatin and pipobroman‐mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin‐B exhibited a superior cytotoxicity profile in cisplatin‐resistant cancer cells. Enhanced activity and the ability to overcome cancer‐induced resistance of Platin‐B was related to adduct formation with intracellular glutathione, followed by the activity of Platin‐B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin‐B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols.     

Revealing the metabolic mechanism of dandelion extract against A549 cells using UPLC-QTOF MS

Dandelion extract exhibits potential anticancer activity and is expected to be a new type of natural anticancer drug. However, the effect mechanism of dandelion extract to lung cancer cells is still unclear. Here, untargeted metabolomics approach based on LC–MS was used to characterize the metabolic responses of A549 cells to dandelion extract exposure and to provide new clues for the antitumor mechanism of dandelion extract from the metabolomics perspective. A total of 16 differentially expressed and time-related metabolites were identified between dandelion extract exposure and control groups. The perturbed metabolic pathways of A549 cells after dandelion extract exposure mainly include the glycerophospholipid metabolism and purine metabolism. These results concluded that dandelion extract may exert anticancer activity by affecting malignant proliferation, disturbing the stability of cell membrane structure, reducing the adhesion of tumor cells to extracellular matrix and fibronectin, and finally inducing tumor cell death.     

Temperature-sensitive polypeptide brushes-coated mesoporous silica nanoparticles for dual-responsive drug release

A multifunctional nanohybrid based on mesoporous silica nanoparticle and biocompatible polypeptide was fabricated for targeted and dual-responsive therapy of tumor cells.