Contemporary Challenges in the Design of Topoisomerase II Inhibitors for Cancer Chemotherapy

Many anticancer drugs are obtained from natural sources. Nature produces a variety of toxic compounds, which are often used as anticancer drugs. Up to now, there are at least 120 species of poisonous botanicals, animals and minerals, of which more than half have been found to possess significant anticancer properties. In spite of their clinical toxicity, they exhibit pharmacological effects and have been used as important traditional Chinese medicines for the different stages of cancer. The article reviews many structures such as alkaloids of Camptotheca acuminata, Catharanthus roseus and Cephalotaxus fortunei, lignans of Dysosma versipellis and Podophyllum emodi, ketones of Garcinia hanburyi, terpenoids of Mylabris and Ginkgo biloba, diterpenoids of Tripterygium wilfordii, Euphorbia fischeriana, Euphorbia lathyris, Euphorbia kansui, Daphne genkwa, Pseudolarix kaempferi and Brucea javanica, triterpenoids of Melia toosendan, steroids of Periploca sepium, Paris polyphylla and Venenum Bufonis, and arsenic compounds including Arsenicum and Realgar. By comparing their related phytochemistry, toxic effects and the recent advances in understanding the mechanisms of action, this review puts forward some ideals and examples about how to increase antitumour activity and/or reduce the side effects experienced with Chinese medicine.

Anticancer Drugs from Traditional Toxic Chinese Medicines

Natural products have been a great source of many small molecule drugs for various diseases. In spite of recent advances in biochemical engineering and fermentation technologies that allow us to explore microorganisms and the marine environment as alternative sources of drugs, more than 70 % of the current small molecule therapeutics derive their structures from plants used in traditional medicine. Natural-product-based drug discovery relies heavily on advances made in the sciences of biology and chemistry. Whereas biology aims to investigate the mode of action of a natural product, chemistry aims to overcome challenges related to its supply, bioactivity, and target selectivity. This review summarizes the explorations of the caged Garcinia xanthones, a family of plant metabolites that possess a unique chemical structure, potent bioactivities, and a promising pharmacology for drug design and development.

/pdf/chemistry-and-biology-of-the-caged-garcinia-xanthones-2o012wnkc8.pdf

Chemistry and biology of the caged Garcinia xanthones.

Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy—a hallmark of cancer—and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transcriptional levels. This extensive understanding of telomerase biology will provide indispensable information for enhancing the efficiency of rational anti-cancer drug design.

https://www.mdpi.com/1422-0067/19/1/13/pdf

Telomerase Inhibitors from Natural Products and Their Anticancer Potential

Inflammation is a natural response of living organisms to the presence of internal and external substances which are recognized by the host as being "non-self" or "foreign invader". It is also a cascade leading to the healing of damaged tissue. Uncontrolled inflammation often results in chronic diseases such as arthritis, autoimmune disorder, cancer, dementia, diabetic, neurodegeneration and vascular disease. The list keeps growing due to the increasing numbers of identified molecular markers that are associated with inflammatory genes or transcription factors. Among various transcription factors, nuclear factor kappa B (NF-kB) is the master switch for proinflammatory genes and transactivates arachidonic acid pathway enzymes when activated. Through evolution, plants have developed vast classes of compounds to fight inflammation. Most of them belong to the chemical group of alkaloids, coumarins, flavonoids, polyphenols and terpenoids. This review article presents and discusses results obtained from literature search on recent findings in plant-derived compounds, which exhibit anti-inflammatory activity in rheumatoid arthritis, allergy and asthma via the suppression of the arachidonic acid pathway. IC(50)s of the compounds obtained from the literature are thus tabulated into six groups of inhibitors based on the enzyme target of phospholipase A2, cyclooxygenase 1 and 2, 5-, 12- and 15-lipoxygenase. Modulation of Th1/Th2 cytokines and histamine/mucus release by some of these enzyme inhibitors are also briefly discussed.

Natural products triggering biological targets--a review of the anti-inflammatory phytochemicals targeting the arachidonic acid pathway in allergy asthma and rheumatoid arthritis.

Although anticancer effect of gambogic acid (GA) and its potential mechanisms were well documented in past decades, limited information is available on the anticancer effect of gambogenic acid (GNA), another major active component of Gamboge. Here we performed a study to determine whether GNA possesses anticancer effect and find its potential mechanisms. The results suggested that GNA significantly inhibited the proliferation of several tumor cell lines in vitro and in vivo. Treatment with GNA dose and time dependently induced A549 cells apoptosis, arrested the cells to G0/G1 phase in vitro and down-regulated the expression of cyclin D1 and cyclooxygenase (COX)-2 in mRNA level. In addition, anticancer effect was further demonstrated by applying xenografts in nude mice coupled with the characteristic of apoptosis in the GNA treated group. Taken together, these observations might suggest that GNA inhibits tumor cell proliferation via apoptosis-induction and cell cycle arrest.

https://www.jstage.jst.go.jp/article/bpb/33/3/33_3_415/_pdf

Gambogenic acid inhibits proliferation of A549 cells through apoptosis-inducing and cell cycle arresting.

To explore gambogenic acid (GNA)-induced apoptosis and underlying mechanism in vivo. A549 nude mice xenografts were used as in vivo model to study anticancer effect of GNA by observing tumor growth curve and weight of the tumor. Ultrastructure of A549 cells treated by GNA was observed by TE. Expression of COX-2 and VEGF were detected by immunohistochemistry. TUNEL assay was applied in examining apoptosis index of tumor cells. The tumor isolated from mice treated by GNA (8, 16 mg kg(-1)) took on a slow growth condition compared with control group. The results suggested that weight and volume of the tumor from experimental groups were remarkably decreased compared with control group (P < 0.05). Ultrastructure change of the tumor, such as vacuolization, abnormal distribution of the heterochromosome, volume of the tumor cells, even apoptotic bodies, were observed in GNA-treated group. While no apparent morphological change was observed in the normal group. Typical apoptotic characteristics could be distinctly observed in the mouse treated by GNA for 20 days and apoptosis index in GNA-treated group was significantly higher than model group. Expression of COX-2 and VEGF were significantly down-regulated in GNA-treated groups in comparison with control group (P < 0.01). These results indicate that GNA could affect the development and progression of A549 cells through inducing apoptosis, mediating the expression of VEGF in vascular cells and COX-2 in tumor cells.

[Gambogenic acid inhibits proliferation of A549 cells through apoptosis-inducing].

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Gambogenic acid inhibits proliferation of A549 cells through apoptosis-inducing and cell cycle arresting.

[Gambogenic acid inhibits proliferation of A549 cells through apoptosis-inducing].