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.     

Xanthones and Cancer: from Natural Sources to Mechanisms of Action

Xanthones are a class of heterocyclic natural products that have been widely studied for their pharmacological potential. In fact, they have been serving as scaffolds for the design of derivatives focusing on drug development. One of the main study targets of xanthones is their anticancer activity. Several compounds belonging to this class have already demonstrated cytotoxic and antitumor effects, making it a promising group for further exploration. This review therefore focuses on recently published studies, emphasizing their natural and synthetic sources and describing the main mechanisms of action responsible for the anticancer effect of promising xanthones.     

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.     

Current landscape and perspective of oncolytic viruses and their combination therapies

Oncolytic virotherapy has become an important strategy in cancer immunotherapy. Oncolytic virus (OV) can reshape the tumor microenvironment (TME) through its replication-mediated oncolysis and transgene-produced anticancer effect, inducing an antitumor immune response and creating favorable conditions for the combination of other therapeutic measures. Extensive preclinical and clinical data have suggested that OV-based combination therapy has definite efficacy and promising prospects. Recently, several clinical trials of oncolytic virotherapy combined with immunotherapy have made breakthroughs. This review comprehensively elaborates the OV types and their targeting mechanisms, the selection of anticancer genes armed in OVs, and the therapeutic modes of action and strategies of OVs to provide a theoretical basis for the better design and construction of OVs and the optimization of OV-based therapeutic strategies.     

tag7 Gene and gene therapy of cancer

Modern gene therapeutic approaches towards the treatment of malignant neoplasms are discussed. Specifically, results of the first experiments on the development of vaccines on the basis of tumor cells modified with various cytokines and activation molecules are described. We compare effectiveness of different cytokines used for modification of tumor cells are made and consider possible mechanisms of vaccine action. The reasons for impossibility of the development of effective endogenous antitumor immunity are examined. The results of comparative analysis of the Tag7 protein antitumor activity are presented. This evidence clearly shows that Tag7 is a promising agent for anticancer therapy.     

Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets

Vitamin E is composed of two groups of compounds: α-, β-, γ-, and δ-tocopherols (TPs), and the corresponding unsaturated tocotrienols (TTs). TTs are found in natural sources such as red palm oil, annatto seeds, and rice bran. In the last decades, TTs (specifically, γ-TT and δ-TT) have gained interest due to their health benefits in chronic diseases, based on their antioxidant, neuroprotective, cholesterol-lowering, anti-inflammatory activities. Several in vitro and in vivo studies pointed out that TTs also exert a significant antitumor activity in a wide range of cancer cells. Specifically, TTs were shown to exert antiproliferative/proapoptotic effects and to reduce the metastatic or angiogenic properties of different cancer cells; moreover, these compounds were reported to specifically target the subpopulation of cancer stem cells, known to be deeply involved in the development of resistance to standard therapies. Interestingly, recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents (i.e., chemotherapeutics, statins, “targeted” therapies) or natural compounds with anticancer activity (i.e., sesamin, epigallocatechin gallate (EGCG), resveratrol, ferulic acid). Based on these observations, different TT synthetic derivatives and formulations were recently developed and demonstrated to improve TT water solubility and to reduce TT metabolism in cancer cells, thus increasing their biological activity. These promising results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment (i.e., in combination with standard therapies) strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed.     

Design,synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents

The naturally occurring coumarins and resveratrol, attract great attention due to their wide range of biological properties, including anticancer, antileukemic, antibacterial and anti-inflammatory activities; moreover, their cancer chemopreventive property have been recently emphasized. A novel class of hybrid compounds, obtained by introducing a substituted trans-vinylbenzene moiety on a coumarin backbone, was synthesized and evaluated for the antitumor profile. A number of derivatives showed a good antiproliferative activity, in some cases higher to that of the reference compound resveratrol. The most promising compounds in this series were 14 and 17, endowed with excellent antiproliferative and proapoptotic activities. The present study suggests that the 7-methoxycoumarin nucleus, together with the 3,5-disubstitution pattern of the trans-vinylbenzene moiety, are likely promising structural features to obtain excellent antitumor compounds endowed with a apoptosis-inducing capability.     

Decision making for promising quinoline‐based anticancer agents through combined methodology

During the development of effective drugs for the treatment of cancer, one of the most important tasks is to identify effective drug candidates having maximum antiproliferation and minimum side effects. This paper considers the problem of selecting the most promising anticancer agents, showing inhibition at low IC₅₀ concentration and low releasing lactate dehydrogenase percentage (cytotoxicity). Recently, we prepared quinoline analogs bearing different functional groups and determined their anticancer potential against the HeLa, C6, and HT29 cancer cell lines using different anticancer assays. Experimentally, seven quinoline derivatives consisting of different substituents were determined as promising anticancer agents. We propose a multicriteria recommendation method to identify the most promising anticancer agents against all tested cell lines with an accurate prediction algorithm according to the available input data. A multicriteria decision‐making methodology (MCDM) was used for the solution of the relevant problem in this study. Both the experimental results and MCDM method indicated that 5,7‐dibromo‐8‐hydroxyquinoline ( 2 ) and 6,8‐dibromo‐1,2,3,4‐tetrahydroquinoline ( 6 ) are the most promising anticancer agents against the HeLa, HT29, and C6 cell lines.     

抗癌肽的作用机制研究进展

近年来癌症的发生率和死亡率呈现逐渐上升的趋势,是威胁人类生命的主要疾病之一。抗癌肽(Anticancer peptides,ACPs)即具有抗肿瘤活性的生物活性肽,其广泛存在于多种生物体内,包括哺乳动物、两栖类动物、昆虫、植物和微生物等。抗癌肽在治疗肿瘤方面具有众多优势,如分子量低、结构简单、高抗癌活性、高选择性、较少的副作用、多种给药方式、不易引起多重耐药性等。文中结合本课题组相关工作,归纳了目前所发现的抗癌肽的作用机制,以期为新型肽类抗肿瘤药物的研发提供一定的方向。     

Novel inhibitors of human histone deacetylases: Design,synthesis and bioactivity of 3-alkenoylcoumarines

Histone deacetylases (HDACs) are well-established, promising targets for anticancer therapy due to their critical role in cancer development. Accordingly, an increasing number of HDAC inhibitors displaying cytotoxic effects against cancer cells have been reported. Among them, a large panel of chemical structures was described including coumarin-containing molecules. In this study, we described synthesis and biological activity of new coumarin-based derivatives as HDAC inhibitors. Among eight derivatives, three compounds showed HDAC inhibitory activities and antitumor activities against leukemia cell lines without affecting the viability of peripheral blood mononuclear cells from healthy donors.     

In vitro studies on genotoxicity and cytotoxicity of the anticancer drugs cisplatin and cofplaton, a caffeine-8-ether plus cisplatinum compound.

The cytotoxic and genotoxic properties of the newly designed anticancer drug 'cofplaton' were investigated. Since cofplaton is a cisplatin (CDDP) plus caffeine compound, the widely applied anticancer drug CDDP alone or in combination with caffeine was studied in parallel. As measured by the MTT test the cytotoxicity of the two drugs was comparable, but cofplaton exhibited significantly fewer genotoxic side effects than CDDP in the chromosome aberration test as well as in the SCE assay. First results from animal studies indicate that cofplaton exerts antitumor activity comparable to CDDP. Because of its relatively low genotoxicity, cofplaton seems to be a promising drug in human anticancer therapy.     

Diallyl Disulfide Suppresses SRC/Ras/ERK Signaling-Mediated Proliferation and Metastasis in Human Breast Cancer by Up-Regulating miR-34a

Diallyl disulfide (DADS) is one of the major volatile components of garlic oil. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human breast cancer have not been elucidated, particularly in vivo. In this study, we demonstrated that the expression of miR-34a was up-regulated in DADS-treated MDA-MB-231 cells. miR-34a not only inhibited breast cancer growth but also enhanced the antitumor effect of DADS, both in vitro and in vivo. Furthermore, Src was identified as a target of miR-34a, with miR-34a inhibiting SRC expression and consequently triggering the suppression of the SRC/Ras/ERK pathway. These results suggest that DADS could be a promising anticancer agent for breast cancer. miR-34a may also demonstrate a potential gene therapy agent that could enhance the antitumor effects of DADS.     

Autophagy induction as an efficient strategy to eradicate tumors

The understanding of the mechanisms of cell-death execution and the role that they play in different diseases opens new therapeutic strategies. Currently, increasing evidence indicates that autophagy is a frequent cell-death mechanism, so the question arises: Could autophagy stimulation be considered an antitumor therapy? Several autophagy inducers have been used as anticancer agents and, although complete tumor eradication has not been demonstrated, the antitumor effect is very promising. We have recently demonstrated that strong autophagy stimulation mediated by the combined generation of cyanide and oxidative stress could efficiently suppress tumor growth in an aggressive brain cancer model such as glioblastoma. We have used the plant enzyme linamarase, which metabolizes the innocuous substrate linamarin to generate cyanide in a continuous and controlled way inducing mitochondrial fragmentation. Glucose oxidase addition induces oxidative stress that increases cell vacuolization. The combination of both insults favors mitochondrial engulfment by vacuoles accelerating cell death that is mediated by autophagy.     

5- 氟尿嘧啶靶向衍生物的研究进展

5-氟尿嘧啶是目前临床上的一线抗肿瘤药物之一,其抗瘤谱广,为高效抗代谢药物,但其首过代谢明显,毒副作用大,治疗剂量与中毒剂量接近,且口服吸收不稳定,半衰期短。因此,对5-氟尿嘧啶进行有效的分子修饰,以克服其缺点,提高其靶向性,最大程度地发挥其活性作用和减轻毒副作用,已成为当今抗癌药物研究的热点。本文根据不同靶向载体,对近年来国内外各种分子修饰的5-氟尿嘧啶靶向衍生物及其抗肿瘤活性研究进行综述。     

5-氟尿嘧啶靶向衍生物的研究进展

5-氟尿嘧啶是目前临床上的一线抗肿瘤药物之一,其抗瘤谱广,为高效抗代谢药物,但其首过代谢明显,毒副作用大,治疗剂量与中毒剂量接近,且口服吸收不稳定,半衰期短。因此,时5-氟尿嘧啶进行有效的分子修饰,以克服其缺点,提高其靶向性,最大程度地发挥其活性作用和减轻毒副作用,已成为当今抗癌药物研究的热点。本文根据不同靶向载体,对近年来国内外各种分子修饰的5-氟尿嘧啶靶向衍生物及其抗肿瘤活性研究进行综述。     

Targeting mitosis exit: A brake for cancer cell proliferation

The transition from mitosis to interphase, referred to as mitotic exit, is a critical mitotic process which involves activation and inactivation of multiple mitotic kinases and counteracting protein phosphatases. Loss of mitotic exit checkpoints is a common feature of cancer cells, leading to mitotic dysregulation and confers cancer cells with oncogenic characteristics, such as aberrant proliferation and microtubule-targeting agent (MTA) resistance. Since MTA resistance results from cancer cells prematurely exiting mitosis (mitotic slippage), blocking mitotic exit is believed to be a promising anticancer strategy. Moreover, based on this theory, simultaneous inhibition of mitotic exit and additional cell cycle phases would likely achieve synergistic antitumor effects. In this review, we divide the molecular regulators of mitotic exit into four categories based on their different regulatory functions: 1) the anaphase-promoting complex/cyclosome (APC/C, a ubiquitin ligase), 2) cyclin B, 3) mitotic kinases and phosphatases, 4) kinesins and microtubule-binding proteins. We also review the regulators of mitotic exit and propose prospective anticancer strategies targeting mitotic exit, including their strengths and possible challenges to their use.     

Comparative analysis of mutagenic potency of 1-nitro-acridine derivatives

The anticancer effect of 1-nitro-9-hydroxyethylamino acridine (C-857), a compound belonging to the 1-nitroacridine class, has been well documented. Despite its therapeutic efficacy, the clinical development of C-857 has been impeded partly due to its high systemic toxicity. In an effort to enhance antitumor efficacy and lower toxicity, derivatives of C-857 have been synthesized with substitutions made at position C-4 and/or an esterified hydroxyl group in side chain at the C-9 position. The introduction of a methyl group at C-4 resulted in C-1748, which has a significantly higher therapeutic efficacy and is being clinically developed as an anticancer agent for solid tumors. The present study was undertaken to correlate the mutagenicity of C-857, C-1748, C-1790, C-1872 and C-1873 with their cytotoxicity and their anti-tumor efficacy. The mutagenicity of these drugs was determined using three Ames Salmonella typhimurium strains TA1537, TA98 and TA102. The bacteria were treated with different molar concentrations, ranging from 10(-3) to 10(-12) M, of the drugs and drug-induced histidine revertants were then counted after a 48 h incubation. C-1748 did not induce any revertants in both TA1537 and TA98 at a dose of 10(-6) M, whereas, C-857 at the same dose induced approximately 842 and approximately 1034 revertants respectively. In TA102, mutagenicity was lower than observed with TA98 and TA1537 with highest revertants observed at 10(-5) M with C-857 (approximately 606) and C-1748 (approximately 108). Higher mutagenicity was observed in the derivatives C-1790, C-1872 and C-1873 compared to C-1748, but lower than C-857. These studies demonstrate that C-1748 has the least mutagenic potential, with a much higher antitumor effect in prostate cancer and is a promising chemotherapeutic agent for clinical development.     

Bacteria in cancer therapy: a novel experimental strategy

Resistance to conventional anticancer therapies in patients with advanced solid tumors has prompted the need of alternative cancer therapies. Moreover, the success of novel cancer therapies depends on their selectivity for cancer cells with limited toxicity to normal tissues. Several decades after Coley's work a variety of natural and genetically modified non-pathogenic bacterial species are being explored as potential antitumor agents, either to provide direct tumoricidal effects or to deliver tumoricidal molecules. Live, attenuated or genetically modified non-pathogenic bacterial species are capable of multiplying selectively in tumors and inhibiting their growth. Due to their selectivity for tumor tissues, these bacteria and their spores also serve as ideal vectors for delivering therapeutic proteins to tumors. Bacterial toxins too have emerged as promising cancer treatment strategy. The most potential and promising strategy is bacteria based gene-directed enzyme prodrug therapy. Although it has shown successful results in vivo yet further investigation about the targeting mechanisms of the bacteria are required to make it a complete therapeutic approach in cancer treatment.     

Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA)

A known side-activity of the oral potassium-sparing diuretic drug amiloride is inhibition of the enzyme urokinase-type plasminogen activator (uPA, K(i)=7 μM), a promising anticancer target. Several studies have demonstrated significant antitumor/metastasis properties for amiloride in animal cancer models and it would appear that these arise, at least in part, through inhibition of uPA. Selective optimization of amiloride's structure for more potent inhibition of uPA and loss of diuretic effects would thus appear as an attractive strategy towards novel anticancer agents. The following report is a preliminary structure-activity exploration of amiloride analogs as inhibitors of uPA. A key finding was that the well-studied 5-substituted analogs ethylisopropyl amiloride (EIPA) and hexamethylene amiloride (HMA) are approximately twofold more potent than amiloride as uPA inhibitors.