New Type Of Anticancer Drug Research Articles

Quantitative Structure-Cytotoxicity Relationship of Chalcones.

Fifteen chalcones were subjected to quantitative structure-activity relationship (QSAR) analysis based on their cytotoxicity and tumor specificity, in order to find their new biological activities. Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal cells to that against tumor cell lines. Potency-selectivity expression (PSE) value was calculated by dividing TS by CC50 against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization. Among 15 chalcone derivatives, (2E)-1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-2-propen-1-one had the highest TS and PSE values, comparable with those of doxorubicin and methotrexate, respectively. This compound also stimulated the cleavage of poly(ADP-ribose) polymerase and caspase-3. Chalone TS values were correlated with molecular shape and polarization rather than the types of substituted groups. None of the compounds had any anti-HIV activity. Chemical modification of the lead compound may be a potential choice for designing new types of anticancer drugs.

Fangchinoline suppresses growth and metastasis of melanoma cells by inhibiting the phosphorylation of FAK.

Melanoma is a malignant tumor with high degree of malignancy, metastasis and high mortality. The etiology of melanoma has not been fully elucidated, and there is no effective drug for the complete treatment of melanoma. In recent years, many traditional Chinese herbal medicines have played an important role in clinical treatment and experimental research on cancer. As a natural product, fangchinoline has the characteristics of enhancing immune function, low toxicity and good liver protection features, so it is considered to be a new type of anticancer drug. In the present study, we found that fangchinoline has inhibitory effects on the proliferation and metastasis of A375 and A875 cells in a concentration-dependent manner. Fangchinoline inhibited the proliferation of A375 and A875 cell activity with IC50 values of 12.41 and 16.20 µM. We also found that fangchinoline could significantly reduce the phosphorylation of Focal adhesion kinase (FAK). In summary, we demonstrated that fangchinoline inhibits the proliferation and metastasis of melanoma cells by suppressing FAK and its downstream signaling pathway. More importantly, we provide a novel mechanism that fangchinoline could be an effective candidate for the treatment of melanoma.

An Update on Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy.

Poly(ADP-ribose)polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills cancer cells by targeting homologous recombination repair defects. Since 2010, important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clinical importance in cancer therapy. Here, we provide an update on PARP-1 inhibitors, focusing on breakthroughs in their clinical applications and investigations into relevant mechanisms of action, biomarkers, and drug resistance. We also provide an update on the design strategies and the structural types of PARP-1 inhibitors. Opportunities and challenges in PARP-1 inhibitors for cancer therapy will be discussed based on the above advances.

Chemical synthesis, docking studies and biological effects of functionalized 1,3-diaryl-2-propen-1-ones on human colon cancer cells

A series of 1, 3-diaryl-2-propen-1-ones was synthesised in order to obtain a new type of anticancer drug, designed with hybrid features to inhibit colon cancer activated receptor. Based on computational modelling and docking studies, potential inhibitors were synthesised and their biological activity evaluated. The structures of newly synthesized compounds were confirmed by 1 HNMR, 13 CNMR and Mass spectrometry. All analogues were evaluated for in vitro cytotoxicity against human colon (caco-2) cancer cell lines. Compounds 1b, 1f-1h, and 2i showed significant cytotoxicity. Chalcones 1b, 1f and 1g were identified as the most potent and selective anticancer agents with IC 50 values <1 µg/mL and 1.5 µg/mL, against caco-2 cell line, respectively. In conclusion, this finding confirms the suitability of indolyl chalcone analogues as candidates for further investigation towards the management of colon cancer related diseases.

Effects of 3-styrylchromones on metabolic profiles and cell death in oral squamous cell carcinoma cells.

4H-1-benzopyran-4-ones (chromones) are important naturally-distributing compounds. As compared with flavones, isoflavones and 2-styrylchromones, there are only few papers of 3-styrylchromones that have been published. We have previously reported that among fifteen 3-styrylchromone derivatives, three new synthetic compounds that have OCH3 group at the C-6 position of chromone ring, (E)-3-(4-hydroxystyryl)-6-methoxy-4H-chromen-4-one (compound 11), (E)-6-methoxy-3-(4-methoxystyryl)-4H-chromen-4-one (compound 4), (E)-6-methoxy-3-(3,4,5-trimethoxystyryl)-4H-chromen-4-one (compound 6) showed much higher cytotoxicities against four epithelial human oral squamous cell carcinoma (OSCC) lines than human normal oral mesenchymal cells. In order to further confirm the tumor specificities of these compounds, we compared their cytotoxicities against both human epithelial malignant and non-malignant cells, and then investigated their effects on fine cell structures and metabolic profiles and cell death in human OSCC cell line HSC-2. Cytotoxicities of compounds 4, 6, 11 were assayed with MTT method. Fine cell structures were observed under transmission electron microscope. Cellular metabolites were extracted with methanol and subjected to CE-TOFMS analysis. Compounds 4, 6, 11 showed much weaker cytotoxicity against human oral keratinocyte and primary human gingival epithelial cells, as compared with HSC-2, confirming their tumor-specificity, whereas doxorubicin and 5-FU were highly cytotoxic to these normal epithelial cells, giving unexpectedly lower tumor-specificity. The most cytotoxic compound 11, induced the mitochondrial vacuolization, autophagy suppression followed by apoptosis induction, and changes in the metabolites involved in amino acid and glycerophospholipid metabolisms. Chemical modification of lead compound 11 may be a potential choice for designing new type of anticancer drugs.

Cancer-selective induction of apoptosis by leczyme.

Sialic acid-binding lectin (SBL) is a multi-functional protein that is isolated from oocytes of Rana catesbeiana. It has both lectin and ribonuclease (enzyme) properties, and therefore is called leczyme. We examined the anti-tumor effects of SBL and discovered that SBL has potential as a new type of anti-cancer drug. SBL causes a cancer-selective induction of apoptosis by multiple signaling pathways whereby RNA is its target. It is suggested that the mitochondrial pathway and endoplasmic reticulum stress-mediated pathway participate in SBL-induced signaling. The synergistic anti-tumor effects with other molecules, such as tumor necrosis factor-related apoptosis ligand and interferon γ, have been reported. In this study, we summarize the effects of SBL and focus on its cancer-selective apoptotic properties. In addition, we present a possible explanation for its cancer specificity.

Sialic acid-binding lectin (leczyme) induces apoptosis to malignant mesothelioma and exerts synergistic antitumor effects with TRAIL

Malignant mesothelioma is a highly aggressive tumor with poor prognosis. An effective drug for treatment of malignant mesothelioma is greatly needed. Sialic acid-binding lectin (SBL) isolated from oocytes of Rana catesbeiana is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity, so it could be developed as a new type of anticancer drug. The validity of SBL for treatment of malignant mesothelioma was assessed using three malignant mesotheliomas and a non-malignant mesothlial cell line. Effectiveness of combinatorial treatment of SBL and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) was also elucidated and characterized. SBL induced tumor-selective cytotoxicity that was attributed to induction of apoptosis. Combinatorial treatment of SBL and TRAIL showed synergistic apoptosis-inducing effect. Additional experiments revealed that Bid was the mediating molecule for the synergistic effect in SBL and TRAIL. These results suggested that SBL could be a promising candidate for the therapeutics for malignant mesothelioma. Furthermore, the combinatorial treatment of SBL and TRAIL could be an effective regimen against malignant mesothelioma.

Downregulation of Hsp70 inhibits apoptosis induced by sialic acid-binding lectin (leczyme)

Heat shock proteins (Hsps) are molecular chaperones that maintain homeostasis of organisms. In regards to the Hsps, many studies have investigated the structure, expression, localization and functions of Hsp70 and Hsc70 including expression in the glycosphingolipid-enriched microdomain (GEM) on the cell surface and involvement in cell death. Sialic acid-binding lectin (SBL) isolated from oocytes of Rana catesbeiana is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity. SBL has potential as a new type of anticancer drug, since it causes cancer-selective induction of apoptosis by multiple signaling pathways in which RNA is its target; and the participation of the mitochondrial pathway and the endoplasmic reticulum (ER) stress-mediated pathway has been suggested. It has also been suggested that receptor(s) for SBL (SBLR) may exist in the GEM on the cell surface. In the present study, we studied the possible involvement of Hsp70 and Hsc70 in SBL-induced apoptosis. We showed that Hsp70 and Hsc70 were expressed on the P388 cell surface similar to SBLR, and their distribution in cells dramatically changed immediately prior to the execution of apoptosis following stimulation of SBL. Functional study of Hsp70 revealed that decreased expression of Hsp70 diminished the apoptosis induced by SBL. It is suggested that Hsp70 participates in the antitumor effect of SBL.

Rubratoxin A specifically and potently inhibits protein phosphatase 2A and suppresses cancer metastasis

Although cytostatin analog protein phosphatase 2A (PP2A)-specific inhibitors are promising candidates of a new type of anticancer drug, their development has been hindered because of their liability. To find new classes of PP2A-specific inhibitors, we conducted a screening with microbial metabolites and found that rubratoxin A, a classical mycotoxin, is a highly specific and potent inhibitor of the enzyme. While rubratoxin A inhibits PP2A at Ki = 28.7 nm, it hardly inhibited any other phosphatases examined. Rubratoxin B, a close analog, also specifically but weakly inhibits PP2A at Ki = 3.1 microM. The inhibition of intracellular PP2A in cultured cells is obviously observed with 20 microM rubratoxin A treatment for 3 h, inducing the overphosphorylation in PP2A substrate proteins. Although rubratoxins and cytostatin differ in the apparent structures, these compounds share similarities in the structures in detail and PP2A-binding manners. Rubratoxin A showed higher suppression of tumor metastasis and reduction of the primary tumor volume than cytostatin in mouse experiments. As a successor of cytostatin analogs, rubratoxin A should be a good compound leading to the development of antitumor drugs targeting PP2A.

Specific Regulation of Point-Mutated K-ras-Immortalized Cell Proliferation by a Photodynamic Antisense Strategy

It has been reported that point mutations in genes are responsible for various cancers, and the selective regulation of gene expression is an important factor in developing new types of anticancer drugs. To develop effective drugs for the regulation of point-mutated genes, we focused on photoreactive antisense oligonucleotides. Previously, we reported that photoreactive oligonucleotides containing 2'-O-psoralenylmethoxyethyl adenosine (2'-Ps-eom) showed drastic photoreactivity in a strictly sequence-specific manner. Here, we demonstrated the specific gene regulatory effects of 2'-Ps-eom on [(12)Val]K-ras mutant (GGT --> GTT). Photo-cross-linking between target mRNAs and 2'-Ps-eom was sequence-specific, and the effect was UVA irradiation-dependent. Furthermore, 2'-Ps-eom was able to inhibit K-ras-immortalized cell proliferation (K12V) but not Vco cells that have the wild-type K-ras gene. These results suggest that the 2'-Ps-eom will be a powerful nucleic acid drug to inhibit the expression of disease-causing point mutation genes, and has great therapeutic potential in the treatment of cancer.

The Research Status of Anti-tumor Effects of Artemisinin and its Derivatives

Artemisinin is a traditional anti-malarial drug. In recent years, many researches indicated that artemisinin and its derivatives have obvious anti-tumor effects. Its mechanisms of anti-tumor lies in cytotoxicity, direct destruction of tumor cells due to oxidative stress reaction, inducing apoptosis, inhibiting of tumor cell proliferation, restraining tumor angiogenesis and performing immunological regulation. Compared with the traditional anti-cancer drugs, artemisinin can selectively inhibit tumor cells and manifestating no cross-resistance with traditional chemotherapeutic agents. Besides it can reverse the phenomenon of multi-drug resistant of tumor cells. Therefore, artemisinin, as an new type of anti-cancer drug, will be applied to a wide range of clinical practice. Key words: Artemisinin; Anti-tumor

Preface

Preface

Selective regulation of mutant K-ras mRNA expression by photo-cross-linking antisense oligonucleotide

It has been reported that point mutations in genes are responsible for various cancers and the selective regulation of the gene expression is an important issue to develop new types of anticancer drugs. In this report, we report new types of antisense molecules that photo-cross-link to target mRNA having a point mutation site in a sequence specific manner. We designed and synthesized photo-reactive antisense oligonucleotides containing a 2'-O-psoralen-conjugated adenosine (2'-Ps-oligo). They contain a psoralen via an ethoxymethylene linker (2'-Ps-eom), a propoxymethylene linker (2'-Ps-pom) and a buthoxymethylene linker (2'-Ps-bom), respectively. We evaluated the photo-cross-linking efficiency and the sequence specificity toward complementary RNA. 2'-Ps-eom showed the highest photo-cross-linking efficiency among 2'-Ps-oligos.

First International Meeting on Quadruplex DNA.

On April 21, thousands of visitors invaded Louisville, KY, including >100 scientists from around the globe. Most of the visitors were there to enjoy the festivities that were in progress as a prelude to the Kentucky Derby. In addition to the Derby celebration, the scientists were there for the First International Meeting on Quadruplex DNA, the first-ever full conference on the roles of quadruplex DNA in biology and chemistry. The field is relatively new. It is quite promising for helping scientists understand cancer and perhaps other diseases, and for the development of new types of anticancer drugs. The meeting opened on Saturday evening with a reception on the 16th floor of the historic Brown Hotel in downtown Louisville. The conference attendees had the pleasant choices of catching up with friends, enjoying the food and drink, or gazing through the large windows of the reception area as the world’s largest fireworks display exploded over the nearby Ohio River (Figure 1). The excitement of being part of the first meeting in this area, and the excellent talks in several different quadruplex research areas, held the interest of the conference group until its end at midday on April 24. No heated discussions took place during the conference sessions; however, areas clearly exist in this relatively new field in which significantly different views must be reconciled.

A Novel Candidate Compound with Urethane Structure for Anticancer Drug Development

Diethyl-4,4'-methylenebis(N-phenylcarbamate) (MDU) is a urethane compound that we originally synthesized, along with three other compounds, to investigate how polyurethane is hydrolysed. We tested the four compounds for cytotoxicity in two Chinese hamster cell lines (CHL and V79) and a human cancer cell line (HeLa S3). MDU showed the strongest cytotoxicity in all the cell lines with an IC50 of around 0.1 microg/ml. We further investigated MDU for its ability to induce chromosome aberrations (CAs) and micronuclei (MN) in CHL cells. MDU induced around 100% polyploid cells at 0.5 microg/ml after 24- and 48-h treatment in the CA test and a significantly increased frequency of micronuclei, polynuclear cells, and mitotic cells in the MN test, suggesting that it may induce numerical CAs. MDU's ability to cause mitotic arrest in CHL cells was greater than that of taxol and colchicine. Based on a COMPARE analysis using JFCR39, a panel of cancer cell lines, we predicted MDU to be a tubulin inhibitor. We confirmed this possibility in nerve growth factor-stimulated PC12 cells as well as in HT1080 cells, in which MDU exhibited the activity to inhibit tubulin polymerization. MDU is simpler in structure than existing anticancer drugs taxol and vincristine and can be synthesized relatively easily. Here we offer MDU as a potential new type of anticancer drug, stable even at room temperature, and inexpensive.

Selective Photo-Cross-Linking of 2′-O-Psoralen-Conjugated Oligonucleotide with Rnas Having Point Mutations

It has been reported that point mutations in genes are responsible for various cancers and the selective regulation of the gene expression is an important issue to develop a new type of anticancer drugs. In this report, we present a new type of antisense molecule that photo-cross-links to an oligoribonucleotide having a point mutation site in a sequence specific manner. 2′-O-psoralen-conjugated adenosine was synthesized in four steps from adenosine and introduced in the middle of an oligodeoxyribonucleotide (2′-Ps-oligo). Compared with 5′-O-psoralen-conjugated oligodeoxyribonucleotide (5′-Ps-oligo), which has a psoralen at the 5′-end, 2′-Ps-oligo more selectively photo-cross-linked to a pyrimidine base of the site of alteration from purine to pyrimidine in the oligoribonucleotide.

Cloning, Sequencing, Analysis, and Heterologous Expression of the Fredericamycin Biosynthetic Gene Cluster from Streptomyces griseus

Fredericamycin (FDM) A, a pentadecaketide featuring two sets of peri-hydroxy tricyclic aromatic moieties connected through a unique chiral spiro carbon center, exhibits potent cytotoxicity and has been studied as a new type of anticancer drug lead because of its novel molecular architecture. The fdm gene cluster was localized to 33-kb DNA segment of Streptomyces griseus ATCC 49344, and its involvement in FDM A biosynthesis was proven by gene inactivation, complementation, and heterologous expression experiments. The fdm cluster consists of 28 open reading frames (ORFs), encoding a type II polyketide synthase (PKS) and tailoring enzymes as well as several regulatory and resistance proteins. The FDM PKS features a KSalpha subunit with heretofore unseen tandem cysteines at its active site, a KSbeta subunit that is distinct phylogenetically from KSbeta of hexa-, octa-, or decaketide PKSs, and a dedicated phosphopantetheinyl transferase. Further study of the FDM PKS could provide new insight into how a type II PKS controls chain length in aromatic polyketide biosynthesis. The availability of the fdm genes, in vivo characterization of the fdm cluster in S. griseus, and heterologous expression of the fdm cluster in Streptomyces albus set the stage to investigate FDM A biosynthesis and engineer the FDM biosynthetic machinery for the production of novel FDM A analogues.

Apicidin is a histone deacetylase inhibitor with anti-invasive and anti-angiogenic potentials

Apicidin has been identified as a histone deacetylase (HDAC) inhibitor. Since HDAC inhibitors are emerging as an exciting new class of potential anti-cancer agents, in the present study, we have examined the inhibitory effect of apicidin on cancer invasion and angiogenesis. Apicidin induced di- and tri-acetylated forms of histone H4 and the morphological alteration in v- ras-transformed mouse fibroblast NIH3T3 cells. Apicidin dramatically inhibited the invasion of v- ras-NIH3T3 and human melanoma A2058 cells and it could be associated with its ability to regulate the activities of matrix metalloproteinases. Interestingly, apicidin strongly inhibited the formation of new vessels on chorioallantoic membrane and the tube formation of ECV304 human vascular endothelial cells. This is the first report to show the anti-angiogenic potential of apicidin and it could be developed as a new type of anti-cancer drug.

Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors.

As soon as the natural polyamines (PAs), putrescine (Put), spermidine (Spd) and spermine (Spm), were recognized as ubiquitous constituents of eukaryotic cells, their involvement in growth-related processes attracted particular interest. The high activities of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) in rapidly growing tissues and cells, particularly in tumour cells, suggested PA biosynthesis as a target for antineoplastic therapy. In the course of the years selective inhibitors have been developed for literally all enzymes of PA metabolism. Some became important as tools in the elucidation of the PA metabolic system, but only few of them were efficient as inhibitors of tumour growth. A major reason for the inefficacy of selective enzyme inhibitors as anticancer drugs is the sophistication of the system, which regulates intracellular PA pools. Selective blockade of a single enzyme induces changes of metabolism and transport, which compensate for the deficit. The selective impairment of tumour growth is in addition hampered by the ubiquitous occurrence of the PAs, their importance in normal functions of nearly all mammalian cells, and the ability or the mammalian organism to utilize exogenous (gastrointestinal) PAs. Among the inhibitors of PA-related enzymes, the ODC inactivator (R, S)-2-(difluoromethyl)ornithine (DFMO) became most famous. Although it was disappointing in most therapeutic attempts to use it as single drug, it has--based on its low toxicity--considerable potential in cancer chemoprevention, and it turned out to be a highly efficient anti-trypanosome agent. Very likely DFMO is suitable to improve the efficacy of some of the current cytotoxic drugs, and it may allow one to create new therapies in combination with other PA-directed drugs. Some of the less selective enzyme inhibitors, particularly those, which inhibit two or more enzymes of PA metabolism, appear to have had a chance to become practically useful, but they have not been developed energetically. Disregarding DFMO, the AdoMetDC inhibitor SAM486A is the only compound for which clinical trials were published. The future of this drug is unclear at present; presumably phase III clinical trials have been discontinued. One of the lessons that had to be learned from the work on selective enzyme inhibitors was that PA metabolism is a much more difficult target, than has been expected on the basis of the simplicity of the PA structures, and the simple reactions involved in their biosynthesis. In order to inhibit tumour growth several reactions or regulatory functions of PA metabolism have to be impaired at the same time. Recent efforts devoted to the development new types of anticancer drugs, which are based on the perturbation of PA metabolism by structural analogues of the natural PAs, take this message into account. These approaches are the topic of the 2nd part of this overview.

Screening of peptides which suppress the proliferation of transformed cells

We have carried out three rounds of screening tests using 239 synthetic tripeptides for the growth-inhibitory activity toward tumor cells and found that those having amino acid sequences of Pro-Thr-Trp or Glu-Arg-Pro effectively inhibit proliferation of transformed cells. These peptides could be the fundamental structures of new types of anticancer drugs.