Oridonin: A promising anticancer drug from China

Oridonin, a diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara, has been proved to possess remarkable anticancer activity, in addition to its potential in antiinflammation and antibacteria. The purpose of this article is to review current progress in oridonin concerned about a relationship between the chemical structure/modifications and its anticancer activity and to discuss the molecular mechanisms underlying its anticancer activity, such as suppression of tumor proliferation and induction of tumor cell death, and the cell signal transduction in anticancer activity of oridonin.     

Interplay between apoptosis and autophagy,a challenging puzzle: New perspectives on antitumor chemotherapies

Autophagy is a mechanism of protection against various forms of human diseases, such as cancer, in which autophagy seems to have an extremely complex role. In cancer, there is evidence that autophagy may be oncogenic in some contexts, whereas in others it clearly contributes to tumor suppression. In addition, studies have demonstrated the existence of a complex relationship between autophagy and cell death, determining whether a cell will live or die in response to anticancer therapies. Nevertheless, we still need to complete the autophagy–apoptosis puzzle in the tumor context to better address appropriate chemotherapy protocols with autophagy modulators. Generally, tumor cell resistance to anticancer induced-apoptosis can be overcome by autophagy inhibition. However, when an extensive autophagic stimulus is activated, autophagic cell death is observed. In this review, we discuss some details of autophagy and its relationship with tumor progression or suppression, as well as role of autophagy–apoptosis in cancer treatments.     

Fabrication of 3D calcium-alginate scaffolds for human glioblastoma modeling and anticancer drug response evaluation

The three-dimensional (3D) cell culture model has been increasingly used to study cancer biology and screen for anticancer agents due to its close mimicry to in vivo tumor biopsies. In this study, 3D calcium(Ca)-alginate scaffolds were developed for human glioblastoma cell culture and an investigation of the responses to two anticancer agents, doxorubicin and cordycepin. Compared to the 2D monolayer culture, glioblastoma cells cultured on these 3D Ca-alginate scaffolds showed reduced cell proliferation, increased tumor spheroid formation, enhanced expression of cancer stem cell genes (CD133, SOX2, Nestin, and Musashi-1), and improved expression of differentiation potential-associated genes (GFAP and β-tubulin III). Additionally, the vascularization potential of the 3D glioblastoma cells was increased, as indicated by a higher expression of tumor angiogenesis biomarker (VEGF) than in the cells in 2D culture. To highlight the application of Ca-alginate scaffolds, the 3D glioblastomas were treated with anticancer agents, including doxorubicin and cordycepin. The results demonstrated that the 3D glioblastomas presented a greater resistance to the tested anticancer agents than that of the cells in 2D culture. In summary, the 3D Ca-alginate scaffolds for glioblastoma cells that were developed in this study offer a promising platform for anticancer agent screening and the discovery of drug-resistant mechanisms of cancer.     

Synthesis,cytotoxicity, and in vivo antitumor activity study of parthenolide semicarbazones and thiosemicarbazones

Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Five compounds were further studied for their antitumor activity in mice. The in vivo result indicated that compound 4d showed both promising antitumor activity against mice colon tumor and small side effects on immune systems. The cell apoptosis and cell cycle distribution of compound 4d were also studied. Molecular docking studies revealed multiple interactions between 4d and NF-κB. Our findings demonstrate the potential of semicarbazones as a promising type of compounds with anticancer activity.     

Rational design of some substituted phenyl azanediyl (bis) methylene phosphonic acid derivatives as potential anticancer agents and imaging probes: Computational inputs,chemical synthesis,radiolabeling, biodistribution and gamma scintigraphy

Bisphosphonates are widely used for treatment of osteoporosis. Recently, they have been reported to be effective anticancer agents. In this work, we designed some substituted phenyl (azanediyl) bis (methylene phosphonic acid) to be tested for their anticancer effect. Both molecular docking and dynamics studies were used to select the top ranked highly scored compounds. The selected hits showed potential in vitro anticancer effect against some cell lines. Biodistribution pattern and gamma scintigraphy were conducted to the most effective derivative (BMBP) after radiolabeling with ^99mTc. Results of biodistribution and scintigraphic imaging of ^99mTc-BMBP in tumor bearing mice showed a notable tumor affinity, and confirmed the targeting affinity of BMBP to the tumor tissues. As a conclusion, BMBP could act as potential anticancer agent and imaging probe.     

Restoration of antitumor immunity through selective inhibition of myeloid derived suppressor cells by anticancer therapies

Accumulating evidence suggests that the success of some anticancer therapies not only relies on their direct cytotoxicity on tumor cells but also on their ability to promote anticancer immune responses. However, immunosuppressive cells such as Myeloid Derived Suppressor Cells (MDSC) that are generated during tumor progression blunt antitumor immune responses and thus represent a major obstacle to the clinical implementation of immunotherapy protocols. We have recently identified 5-Fluorouracil (5-FU) as an anticancer agent that selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination of MDSC by 5-FU increased IFNγ secretion by tumor specific CD8(+) T cells infiltrating the tumor and promoted T-cell dependent antitumor responses in vivo, suggesting that some anticancer therapies can reverse tumor-mediated immunosuppression. Here, we review the molecular pathways leading to the induction of MDSC in cancer and discuss how different anticancer agents successfully target these cells in vivo, thereby restoring potent anticancer immunity.     

Hsp70 chaperone and the prospects of its application in anticancer therapy

Major stress protein Hsp70 is known to possess two important properties: ATP-dependent activity and protective activity; these two are thought to play a significant role in anticancer therapy. Many malignant tumors contain high amounts of intracellular Hsp70. Moreover, many anticancer drugs themselves are able to elevate Hsp70 expression in tumor cells. Since Hsp70 was found to disturb many signal pathways of apoptosis in many points, the high chaperone expression may lead to an increased resistance of tumor cells to anticancer drugs. On the other hand, when overexpressed by a certain mechanism, Hsp70 is able to emerge at the cell surface by itself or together with tumor antigens and present these to immune cells T-lymphocytes and natural killers, in such a manner that makes cancer cell recognized and abolished. These properties make Hsp70 very promising instrument in designing some novel anticancer vaccines.     

An Automatable Hydrogel Culture Platform for Evaluating Efficacy of Antibody‐Based Therapeutics in Overcoming Chemoresistance

The microenvironment plays a major role in conferring chemoresistance to cancer cells. In order to better inform clinical response to chemoresistance, preclinical models that recapitulate its hallmark features are needed to enable screening for resistance‐specific therapeutic targets. A novel platform for seeding cancer cells in 3D hydrogels is presented utilizing derivatives of chitosan and alginate that, critically, is amenable to high throughput screening: cell seeding in hydrogels, media changes, dosing of anticancer compounds, and cell viability assays are all automated using a standard and commercially available liquid handling robot. Culture in these hydrogels elicits resistance in ovarian, lung, and prostate cancer cells to treatment by doxorubicin and paclitaxel. In correlation, proteomics analysis of SKOV3 cells cultured in 3D reveals enrichment of proteins associated with extreme drug resistance including HMOX1 and ALDH2. Subsequently, therapeutic antibodies targeted to tumor‐associated antigens upregulated in 3D cultures are shown to have higher efficacy compared to 2D cultures. Collectively, this automated 3D cell culture platform provides a powerful tool with utility in identification of drugs that may overcome chemoresistance.     

A structured light-based system for scanning subcutaneous tumors in laboratory animals

Tumor size or volume is often the primary endpoint in preclinical efficacy studies of anticancer drugs. Efficient and accurate measurement of such tumors is crucial to rapid evaluation of novel drug candidates. Currently available techniques for acquiring high-throughput data on tumor volume are time-consuming and prone to various inaccuracies and errors. The laser-scanning technology we describe here provides a convenient, high-throughput system for tumor measurement that reduces interoperator variability and bias while providing automated data collection, processing and analysis.     

Caspase-dependent and -independent death pathways in cancer therapy

The majority of current anticancer therapies induce tumor cell death through the induction of apoptosis. Alterations in the apoptotic pathways may determine tumor resistance to these therapies. Activation of the proteolytic cascade involving caspase family members is a critical component of the execution of cell death in apoptotic cells. However, recent studies suggest that cell death can proceed in the absence of caspases. In this review we describe the role of caspase-dependent and -independent pathways as targets for anticancer treatment; better understanding of diverse modes of tumor cell death will help to avoid ineffective treatment and provide a molecular basis for the new strategies targeting caspase-independent death pathways in apoptosis-resistant forms of cancer.     

Antiangiogenic and anticancer potential of unsaturated vitamin E (tocotrienol)

Several lines of evidence support the beneficial effect of tocotrienol (T3; an unsaturated vitamin E) on inhibition of tumor development. Many factors, including decrease in oxidative stress and modulation of cell signaling pathways in tumor and endothelial cells, have been implicated in such anticancer action of T3, while the in vivo potency and exact intracellular mechanisms for the anticancer properties of T3 remain not fully understood. We have hypothesized that the inhibitory effect of T3 on cancer may be attributable to the antiangiogenic activity of T3, and we found that T3 acts as a potent regulator of growth-factor-dependent signaling in endothelial cells and as an antiangiogenic agent minimizing tumor growth. In this work, we review the history and biological action (i.e., anticancer) of vitamin E and describe current research on the antiangiogenic effects of T3 and its mechanisms.     

Nox4-dependent ROS modulation by amino endoperoxides to induce apoptosis in cancer cells

Tumor metastasis is the main cause of death in cancer patients. Anoikis resistance is one critical malefactor of metastatic cancer cells to resist current clinical chemotherapeutic treatments. Although endoperoxide-containing compounds have long been suggested as anticancer drugs, few have been clinically employed due to their instability, complex synthesis procedure or low tumor cell selectivity. Herein, we describe a one-pot strategy to synthesize novel amino endoperoxides and their derivatives with good yields and stabilities. In vitro cell-based assays revealed that 4 out of the 14 amino endoperoxides selectively induce metastatic breast carcinoma cells but not normal breast cells to undergo apoptosis, in a dose-dependent manner. Mechanistic studies showed that the most potent amino endoperoxide, 4-Me, is selective for cancer cells expressing a high level of Nox4. The anticancer effects are further shown to be associated with reduced O₂⁻:H₂O₂ ratio and increased ·OH level in the cancerous cells. Animal study showed that 4-Me impairs orthotopic breast tumor growth as well as tumor cell metastasis to lymph nodes. Altogether, our study suggests that anticancer strategies that focus on redox-based apoptosis induction in tumors are clinically viable.     

Artocarpin induces cell apoptosis in human osteosarcoma cells through endoplasmic reticulum stress and reactive oxygen species

Osteosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. However, because of side effects and drug resistance in chemotherapy and the insufficiency of an effective adjuvant therapy for osteosarcoma, it is necessary to research novel treatments. This study was the first to investigate the anticancer effects of the flavonoid derivative artocarpin in osteosarcoma. Artocarpin induced cell apoptosis in three human osteosarcoma cell lines—U2OS, MG63, and HOS. Artocarpin was also associated with increased intracellular reactive oxygen species (ROS). Mitochondrial dysfunction was followed by the release of cytochrome c from mitochondria and accompanied by decreased antiapoptotic Bcl-2 and Bcl-xL and increased proapoptotic protein Bak and Bax. Artocarpin triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol calcium levels and increased glucose-regulated protein 78 and 94 expressions, and also increased calpains expression and activity. Animal studies revealed a dramatic 40% reduction in tumor volume after 18 days of treatment. This study demonstrated a novel anticancer activity of artocarpin against human osteosarcoma cells and in murine tumor models. In summary, artocarpin significantly induced cell apoptosis through ROS, ER stress, mitochondria, and the caspase pathway, and may thus be a novel anticancer treatment for osteosarcoma.     

Enhancement of cisplatin-induced apoptosis by saffron in human lung cancer cells

BackgroundCisplatin is a prevalent chemotherapeutic agent, and it has been used extensively to treat lung cancer. However, its clinical efficacy is hampered by its safety profile and dose-limiting toxicity. Saffron is a natural product that has shown significant anticancer effects. The combination treatment of saffron with chemotherapeutic agents has been considered a new strategy.MethodsHerein, saffron extract as a natural anticancer substance was combined with cisplatin to assess their combined efficacy against tumor development in vitro. In A549 and QU-DB cell lines, the combined effect of the saffron extract with cisplatin led to a significant reduction in cell viability as compared to cisplatin alone.ResultsAfter 48 h incubation a considerable reduction in ROS levels in the QU-DB cell line upon treatment with cisplatin in the presence of saffron extract in comparison with cells treated with cisplatin alone. Furthermore, apoptosis increased significantly when in cells treated with cisplatin in combination with saffron extract compared to cisplatin alone.ConclusionOur data establish that the combination of saffron extract as a natural anticancer substance with cisplatin leads to improved cell toxicity of cisplatin as an anticancer agent. Therefore, the saffron extract could be potentially used as an additive to enable a reduction in cisplatin dosages and its side effects.     

Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1

The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.     

3-D culture in synthetic extracellular matrices: New tissue models for drug toxicology and cancer drug discovery

The new sECM biomaterials have been successfully used to perform 3D cell culture, drug and growth factor release, drug toxicity testing, and to develop a new anticancer drug evaluation model. The ready availability of these materials should facilitate progress in understanding regulation of cellular physiology as influenced by endogenous signals or exogenous pharmaceutical agents in 3-D tissue-like cell cultures. Importantly, the use of primary hepatocytes and soon, human liver stem cells, cultured in Extracel™ will expedite drug toxicity testing in vitro and in vivo. In addition, the application of the orthotopic engineered tumor xenograft model using Extracel™-containing tumor cells in nude mice should improve the selection of new anticancer agents that will show clinical efficacy in cancer patients.     

A 3D Fibrous Scaffold Inducing Tumoroids: A Platform for Anticancer Drug Development

The development of a suitable three dimensional (3D) culture system for anticancer drug development remains an unmet need. Despite progress, a simple, rapid, scalable and inexpensive 3D-tumor model that recapitulates in vivo tumorigenesis is lacking. Herein, we report on the development and characterization of a 3D nanofibrous scaffold produced by electrospinning a mixture of poly(lactic-co-glycolic acid) (PLGA) and a block copolymer of polylactic acid (PLA) and mono-methoxypolyethylene glycol (mPEG) designated as 3P. Cancer cells cultured on the 3P scaffold formed tight irregular aggregates similar to in vivo tumors, referred to as tumoroids that depended on the topography and net charge of the scaffold. 3P scaffolds induced tumor cells to undergo the epithelial-to-mesenchymal transition (EMT) as demonstrated by up-regulation of vimentin and loss of E-cadherin expression. 3P tumoroids showed higher resistance to anticancer drugs than the same tumor cells grown as monolayers. Inhibition of ERK and PI3K signal pathways prevented EMT and reduced tumoroid formation, diameter and number. Fine needle aspirates, collected from tumor cells implanted in mice when cultured on 3P scaffolds formed tumoroids, but showed decreased sensitivity to anticancer drugs, compared to tumoroids formed by direct seeding. These results show that 3P scaffolds provide an excellent platform for producing tumoroids from tumor cell lines and from biopsies and that the platform can be used to culture patient biopsies, test for anticancer compounds and tailor a personalized cancer treatment.     

Evaluating Therapeutic Efficacy against Cancer Stem Cells: New Challenges Posed by a New Paradigm

Current measures of anticancer drug efficacy reflect bulk cell killing and are poorly suited to detect activity against cancer stem cells (CSCs), which sustain tumor growth. The CSC paradigm necessitates a reexamination of methodologies used to evaluate clinical efficacy of anticancer therapies, as well as strategies employed during preclinical drug development.     

Anticancer drugs up-regulate HspBP1 and thereby antagonize the prosurvival function of Hsp70 in tumor cells

The 70-kDa heat shock protein (Hsp70) is up-regulated in a wide variety of tumor cell types and contributes to the resistance of these cells to the induction of cell death by anticancer drugs. Hsp70 binding protein 1 (HspBP1) modulates the activity of Hsp70 but its biological significance has remained unclear. We have now examined whether HspBP1 might interfere with the prosurvival function of Hsp70, which is mediated, at least in part, by inhibition of the death-associated permeabilization of lysosomal membranes. HspBP1 was found to be expressed at a higher level than Hsp70 in all normal and tumor cell types examined. Tumor cells with a high HspBP1/Hsp70 molar ratio were more susceptible to anticancer drugs than were those with a low ratio. Ectopic expression of HspBP1 enhanced this effect of anticancer drugs in a manner that was both dependent on the ability of HspBP1 to bind to Hsp70 and sensitive to the induction of Hsp70 by mild heat shock. Furthermore, anticancer drugs up-regulated HspBP1 expression, whereas prevention of such up-regulation by RNA interference reduced the susceptibility of tumor cells to anticancer drugs. Overexpression of HspBP1 promoted the permeabilization of lysosomal membranes, the release of cathepsins from lysosomes into the cytosol, and the activation of caspase-3 induced by anticancer drugs. These results suggest that HspBP1, by antagonizing the prosurvival activity of Hsp70, sensitizes tumor cells to cathepsin-mediated cell death.     

2-Benzoylbenzofuran derivatives possessing piperazine linker as anticancer agents

A series of novel 2-benzoylbenzofuran derivatives possessing piperazine linker have been prepared, and their in vitro anticancer activity against a panel of human tumor cell lines by MTT assay were evaluated. The results demonstrated that tertiary amine derivatives exhibited better cytotoxic activity, and SAR study revealed that electron-donating substituents on the phenyl ring of the derivatization functionality contributed to potent anticancer activities. Among them, compounds 6, 9, 11, 18, 23 and 25 displayed both better anti-tumor activity and lower cytotoxic effect on human normal liver cell L02. Further apoptosis analysis showed that compound 18 significantly induced apoptosis in A549 cell, which was considered as the most potent anticancer agent.