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Combinatorial Biosynthesis of Anticancer Natural Products

Metro, January 2018
She took 8g of turmeric tablets every day for years without further treatment, and has now shocked doctors. ‘To the best of our knowledge, this is the first report in which curcumin has demonstrated an objective response in progressive disease in the absence of conventional treatment,’ her doctors, from Barts Health NHS Trust in London, wrote in the British Medical Journal Case Reports. ‘In the absence of further antimyeloma treatment the patient plateaued and has remained stable for the past five years with good quality of life.’ Turmeric is widely used in Asian cuisine and helps create distinctive colour in curries – but it would be impossible to cure myeloma with regular cooking turmeric. It would be impossible to treat cancer with regular kitchen turmeric, as it contains just 2% curcumin.

According to the mechanism of oncolytic virus, theprimary character of oncolytic adenovirus is its ability ofinfecting cancer cells, selectively replicating within them andinducing cell death. To detect the antitumor activity of SG511,HeLa, SW480, Panc-1 and HT-29 cancer cell lines were infected withSG511 at the indicated MOIs. At 48 h after viral infection, cellswere stained with crystal violet solution. Results showed thatSG511 killed all tested cancer cell lines effectively in adose-dependent way. Tumor cells were almost complete eliminatedwhen the virus was used at a MOI of 40 (). Next, we compared the inhibitoryeffect of SG511 to that of Ad5/11 (a fiber chimeric non-replicatingvirus) by an MTT assay ().SG511 induced concentration-dependent cell death in HT-29 cells,whereas Ad5/11 did not cause any detectable cytototoxic effect. Weexamined effects of SG511 and cisplatin on human normal hepaticcell line L-02. As shown in , the treatment of cisplatin alone at 2 μg/ml and 4 μg/mlelicited a marked growth inhibition. In contrast, SG511 did notresult in obvious cytotoxicity toward normal cells. Furthermore,combined use of cisplatin and oncolytic virus SG511 had onlyslightly greater cytotoxic effect compared with cisplatin alone. Wefurther investigated the cytotoxicity of SG511 against human normalMSCs. As shown in , SG511 atthe indicated dosage did not apparently affect the viability ofhuman MSCs. These data suggest that SG511 is an idealtumor-specific replicative adenovirus for virotherapy ofcancer.

Therefore, having more fibers through an anti cancer diet aids in overcoming these problems.

Combinatorial Biosynthesis of Natural Products - …

In addition, the omega-3 fats have the power to alleviate tumor resistance due to which they are required for an effective brain cancer treatment.

We investigated the potential molecular mechanism ofsensitization of cancer cells to SG511/cisplatin combination, byexamining possible alterations in the expression levels ofproapoptotic and antiapoptotic signaling molecules. As observed inthe western blots (),individual treatment with cisplatin at 4 μg/ml did not inducediscernible changes in the expression of Bcl-2, Bid, Mcl-1, Bax,and Bim in HT-29 and HeLa cells. In marked contrast, treatment withSG511 at a MOI of 40 downregulated the levels of multidomainanti-apoptotic proteins Bcl-2, and Mcl-1, and upregualted the levelof pro-apoptotic Bax. Cleavage of BH3-only pro-apoptotic proteinBid and Bim accumulation was also observed in cells treated withSG511. These conformational changes were also observed in HeLacells after treatment with SG511 combined with cisplatin. However,these two agents, alone or in combination, had no effect on theexpression of Bcl-xL in the cancer cell lines.

Molecular Medicine Reports, December 2017
Tobacco smoke is a major risk factor for lung cancer. Epithelial‑mesenchymal transition (EMT) is decisive in cancer invasion and metastasis, and therefore promotes cancer progression. The chemopreventive effect of curcumin on carcinogenesis has been reported in vivo and in vitro. Curcumin treatment inhibited tobacco smoke‑induced MAPK/AP‑1 activation, including ERK1/2, JNK and p38 MAPK pathways, and AP‑1 proteins, and reversed EMT alterations in lung tissue. The results of the present study provide new insights into the molecular mechanisms of tobacco smoke‑associated lung cancer and may open up new avenues in the search for potential therapeutic targets in lung tumorigenesis.

Combinatorial biosynthesis of ‘unnatural’ natural products…

Oxford University Press, December 2017
Over the past few decades, curcumin, a common food additive, has been identified as a potential anti-inflmmatory and anti-cancer compound. Curcumin is a phenolic compound extracted from the Curcuma longa plant, and was traditionally used as a spice for improving flavor and color into dishes of various Asian countries. Curcumin’s health benefits are not a new or surprising finding — the brightly colored compound has been used in Ayurvedic medicine for centuries for its potent anti-inflammatory and anti-tumor properties — but the fundamental mechanisms underlying its anti-cancer potential still remain an active area of interrogation. Intriguingly, curcumin has been shown to sensitize multiple cancers to chemotherapy drugs, and several recent studies have reported that curcumin is able to specifically target cancer stem cells. . As suggested by other groups, not only did we demonstrate that curcumin was able to enhance the sensitivity of gemcitabine in these resistant cells, we found that curcumin was also able to inhibit the growth of cancer stem cells. In our study, we also discovered that curcumin was regulating a class of non-coding RNA called “long non-coding RNAs” (lncRNAs). LncRNA is a relatively newly discovered type of non-coding RNA — RNA which does not make protein — found to be dysregulated in most cancers. We discovered that curcumin inhibits the expression of one of the most well-known lncRNA-based oncogenes, a gene that drives cancer, called PVT1. This lncRNA drives tumor progression through the regulation of another well-recognized oncogene, called EZH2. EZH2 is one of the oncogenes known to be involved in drug resistance and is identified to be a potential drug-able target. Though the generation of specific EZH2 inhibitors remains challenging, the findings from our study indicate that curcumin could be used to inhibit the expression of EZH2, as well as the non-coding RNA that regulates EZH2. Considering that curcumin is a commonly available health supplement, it presents itself as a non-toxic compound and incredibly cost-effective compound for the potential treatment of cancer patients.

For these reasons, it is vital for cancer patients to have a good strong immune system which improves treatment outcome.

Why Natural Products?

Natural products remain the best sources of drugs and drug leads

Natural products remain the best sources of drugs and drug leads, and this remains true today despite the fact that many pharmaceutical companies have deemphasized natural products research in favor of HTP screening of combinatorial libraries during the past 2 decades. From 1940s to date, 131 (74.8%) out of 175 small molecule anticancer drugs are natural product-based/inspired, with 85 (48.6%) being either natural products or derived therefrom. From 1981 to date, 79 (80%) out of 99 small molecule anticancer drugs are natural product-based/inspired, with 53 (53%) being either natural products or derived therefrom. Among the 20 approved small molecule New Chemical Entities (NCEs) in 2010, a half of them are natural products.

Natural products possess enormous structural and chemical diversity that is unsurpassed by any synthetic libraries. About 40% of the chemical scaffolds found in natural products are absent in today’s medicinal chemistry repertoire. Based on various chemical properties, combinatorial compounds occupy a much smaller area in molecular space than natural products. Although combinatorial compounds occupy a well-defined area, natural products and drugs occupy all of this space as well as additional volumes. Most importantly, natural products are evolutionarily optimized as drug-like molecules. This is evident upon realization that natural products and drugs occupy approximately the same molecular space.

Natural products represent the richest source of novel molecular scaffolds and chemistry. No one can predict, in advance, the details of how a small molecule will interact with the myriad of targets that we now know drive fundamental biological processes. The history of natural product discovery is full of remarkable stories of how the discovery of a natural product profoundly impacted advances in biology and therapy. For instance, Taxol's impact on tubulin polymerization, and correlation to antitumor action or rapamycin's binding to mTOR and the ramifications of mTOR inhibitors could never be predicted . The discovery of new natural products promises significant advances not only in chemistry, but also, biochemistry and medicine.

Natural products are significantly underrepresented in current small molecule libraries

In spite of the great success of natural products in the history of drug discovery, natural products are significantly underrepresented in current small molecule libraries. Challenges of natural products in drug discovery and development include (i) extremely low yields, (ii) limited supply, (iii) complex structures posing enormous difficulty for structural modifications, and (iv) complex structures precluding practical synthesis. These difficulties lead to the pharmaceutical industry to embrace new technologies in the past two decades, particularly combinatorial chemistry, at the detriment to interest in natural product discovery.

Microbial natural products as preferred sources of new drugs and drug leads

Microbial natural products have several intrinsic properties favoring their consideration in drug discovery and development. Microbial natural products can be produced by large-scale fermentation. Microorganisms can be engineered to overproduce the desired natural products hence to solving the supply bottleneck. Microbial natural product analogues can be produced by metabolic pathway engineering, thereby providing a focused library for structure-activity-relationship studies. The vast, untapped, ecological biodiversity of microbes holds great promise for the discovery of novel natural products, thereby improving the odds of finding novel drug leads.

The exponential growth in cloning and characterization of natural product biosynthetic machinery from microbes in the last two decades has unveiled unprecedented molecular insights into natural product biosynthesis, including the observation that genes for natural product biosynthesis are clustered in the microbial genome and that variations of a few common biosynthetic machineries can account for vast structural diversity observed for natural products. These findings have fundamentally changed the landscape of natural product research by enabling the revision of known natural product structures, the prediction of yet-to-be isolated novel compounds on the basis of gene sequences, and the systematic generation of “unnatural” natural products by manipulating genes governing their biosynthesis (also known as combinatorial biosynthesis).

Whole genome sequencing has revealed far more biosynthetic gene clusters than actual metabolites currently known for a given organism, suggesting that the biosynthetic potential for natural products in microorganisms is greatly under-explored by traditional natural product discovery methods. Among the whose genomes have been sequenced, every one of them has the potential to produce up to 30 natural products on average, and this optimism has already translated into the discovery of new natural products by fermentation optimization from strains that otherwise were not previously known as natural product producers.

Only 1% of the microbial community has been estimated to be cultivated in the lab, implying that the vast biodiversity of microbial natural products remains underappreciated. Emerging new cultivating techniques, culture-independent methods by expressing gene clusters in model heterologous hosts, and diligent effort and innovative approaches in novel microbial strain collection, identification, and classification have started to permit access to these previously inaccessible natural product resources.

The future of microbial natural product drug discovery and development remains bright. (i) Advances in DNA sequencing will greatly facilitate genome sequencing and genomics-based natural products discovery. (ii) Advances in DNA synthesis and synthetic biology will greatly facilitate natural product pathway reconstruction, engineering, and expression in model or industrial hosts for natural product production. (iii) Advances in HTS will further enable rapid screening of natural product libraries for an ever broader range of biological application. (iv) Advances in isolation technologies, analytic methods, automatic robotics, and database management will greatly facilitate natural products library construction. (v) Environmental concerns will further favor bio-based natural products drug discovery and development processes, i.e., fermentation, metabolic pathway engineering, and renewable resources.

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Natural products as leads to anticancer drugs | SpringerLink

Combinatorial Biosynthesis of Natural Products

Sci-News, February 2018
Curcumin has previously been shown to have anti-inflammatory and antioxidant properties in lab studies. It also has been suggested as a possible reason that senior citizens in India, where curcumin is a dietary staple, have a lower prevalence of Alzheimer’s disease and better cognitive performance. “The people who took curcumin experienced significant improvements in their memory and attention abilities, while the subjects who received placebo did not,” Dr. Small said. “In memory tests, the people taking curcumin improved by 28% over the 18 months. Those taking curcumin also had mild improvements in mood, and their brain PET scans showed significantly less amyloid and tau signals in the amygdala and hypothalamus than those who took placebos.”

Anticancer agents from natural products [electronic resource]

PSA is enzyme released in the prostate of men and the level of PSA becomes very high in men who are suffering from prostate cancer.
Before supplementation (Pomegranate Juice) was given to them, the average time it took for PSA levels to double (become twice as high) was 15 months.
When pre-treatment and post-treatment patient serum was compared, there was a marked improvement in apoptosis, in-vitro cell proliferation and oxidative stress.

Anticancer agents from natural products [electronic ..

Blasting News, February 2018
Turmeric -- The spice that gives curry that yellow coloring. This powerful herb's main ingredient is curcumin, a natural anti-inflammatory which the body needs to fight off bacteria that are harmful. Along with the increased production of antioxidants and a great way to fight heart disease, another important benefit of taking Turmeric is the growth hormone called Brain-Derived Neurotrophic Factor. According to the US National Library of Medicine, decreased levels of BDNF can lead to brain disease and decreased functions in the brain. Curcumin can increase levels of BDNF, which can delay or even reverse many brain diseases or age-related decreases in brain function. You will want to add this to your supplement routine, as curcumin makes up only three percent of Turmeric, so taking it as a supplement is better.

in natural product-based anticancer drug ..

Doctor Oz, February 2018
UCLA researchers find consumption of curcumin helps mood and memory. Forty adults with mild memory complaints were randomly selected to ingest curcumin twice daily or a placebo for 18 months. They underwent cognitive assessments and PET scans to test amyloid in the brain, which is associated with negative effects on memory and emotional functions. Those taking curcumin improved their memory tests by twenty-eight percent, demonstrated mild mood improvements, and showed far smaller levels of amyloid than the placebo group. A follow-up study will explore the possibility of curcumin possessing antidepressant effects and whether it can help your genetic risk for Alzheimer’s. These findings back up the far lower rate of Alzheimer’s in India’s senior citizens, whose diet is high in curcumin.

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