Mitaplatin as a better anticancer agent.......

In continuation of my update on Platinum compounds as anticancer drugs, I find  this one more interesting info to share with. MIT chemists have developed a new platinum compound that is as powerful as the commonly used anticancer drug cisplatin but better able to destroy tumor cells.

As per the claim by the researchers, glycolytic metabolism of most solid tumors, known as the Warburg effect, is associated with resistance to apoptosis that enables cancer cells to survive. Dichloroacetate (DCA) is an anticancer agent that can reverse the Warburg effect by inhibiting a key enzyme in cancer cells, pyruvate dehydrogenase kinase (PDK), that is required for the process. DCA is currently not approved for cancer treatment in the USA. With this idea behind researchers have prepared the new compound by combining dichloroacetate, DCA and cisplatin. Mitaplatin, thus obtained has two DCA units which are appended to the axial positions of a six-coordinate Pt (IV) center.

As per the claim by the authors, the negative intracellular redox potential reduces the platinum to release cisplatin, a Pt (II) compound, and two equivalents of DCA. By a unique mechanism, mitaplatin thereby attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt (IV) compounds and is comparable to that of cisplatin.

Mitaplatin alters the mitochondrial membrane potential gradient of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular reduction of mitaplatin enters the nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as an anticancer drug. These properties of mitaplatin are manifest in its ability to selectively kill cancer cells cocultured with normal fibroblasts and to partially overcome cisplatin resistance. Further studies like mice transplanted with human tissues are to be substantiated, in my opinion its a good achievement...

Ref : http://www.pnas.org/content/early/2009/12/09/0912276106.abstract?related-urls=yes&legid=pnas;0912276106v1

Caffeine-based compound with small amount of gold could be used as anticancer agent

The side effects of ingesting too much caffeine - restlessness, increased heart rate, having trouble sleeping - are well known, but recent research has shown that the stimulant also has a good side. It can kill cancer cells. Now, researchers report in the ACS journal Inorganic Chemistry that combining a caffeine-based compound with a small amount of gold could someday be used as an anticancer agent.

Angela Casini, Michel Picquet and colleagues note that caffeine and certain caffeine-based compounds have recently been in the spotlight as possible anticancer treatments. But drinking gallons of coffee, sodas and energy drinks isn't the solution. And the regular caffeine in these drinks would start to have negative effects on healthy cells, too, at the levels necessary to kill cancerous ones. Gold also can wipe out cancer cells, but, like caffeine, it can harm healthy cells. So, the research team put the two together into certain configurations to see whether the new caffeine-based gold compounds could selectively stop cancer cells from growing without hurting other cells.

They made a series of seven new compounds, called caffeine-based gold (I) N-heterocyclic carbenes, in the laboratory and studied them. The scientists found that, at certain concentrations, one of the compounds of the series selectively killed human ovarian cancer cells without harming healthy cells. In addition, the compound targeted a type of DNA architecture, called "G-quadruplex," that is associated with cancer.

Ref : http://pubs.acs.org/doi/abs/10.1021/ic403011h?prevSearch=Angela%2BCasini&searchHistoryKey=

Caffeine-based compound with small amount of gold could be used as anticancer agent

Smart anticancer 'nanofiber mesh'

A MANA research team has developed a new nanofiber mesh which is capable of simultaneously realizing thermotherapy (hyperthermia) and chemotherapy (treatment with anticancer drugs) of tumors. They succeeded in efficiently inducing natural death (apoptosis) of epithelial cancer cells.

Ref : http://onlinelibrary.wiley.com/doi/10.1002/adfm.201300746/abstract;jsessionid=A14E178EC5E6FC5D367A7C71FF0D30BC.d02t01



Smart anticancer 'nanofiber mesh'

ProstaCaid (33-ingredient comprehensive polyherbal preparation) against prostate cancer......

We have seen  many benefits of natural products rich in  Quercetin,   Epigallocatechin gallate (EGCG) and many other polyphenol antioxidant from natural products like green tea, broccoli peaches and plums. Interestingly, now researchers from  Columbia University have come up with an interesting finding, i.e., ProstaCaid is a 33-ingredient comprehensive polyherbal preparation with supplements of vitamin C, vitamin D3, zinc, selenium, quercitin, 3,3′-diinodolymethane (DIM), and lycopene was able to stop abnormal cell growth and induce apoptosis (programmed cell death) in both hormone sensitive and hormone resistant prostate cancer cell lines at unusually low concentrations, which makes the findings more significant...

Herbal extracts include the extracts from turmeric root, saw palmetto berry, grape skin, pomegranate, pumpkin seed, pygeum bark, sarsaparilla root, green tea, and Japanese knotweed. Hence, it is rich in natural polyphenols, including quercetin, resveratrol, epigallocatechin gallate (EGCG), and ellagic acid, which have previously demonstrated anticancer potential. The unique formula contains 3 medicinal mushrooms grown on an herbal-enhanced medium. The mushrooms included are Phellinus linteus, Ganoderma lucidum, and Coriolus versicolor, each with known anticancer properties.

Researchers claim that, ProstaCaid was designed based on constituents that exhibit antiprolifetaive, antioxidant, and apoptotic activities; however, its efficacy and the mechanisms of action are yet to be examined. Researchers looked at the effectiveness of the preparation in suppressing several types of prostate cancer cell lines in culture and attempt to delineate the mechanism of action for justification in pursuing animal to determine efficicacy invivo.

Researchers conclude that, the anticancer activity of ProstaCaid may be ascribed to its polyphenolic flavonoids and curcuminoids derived from various herbs as well as other supplements, such as DIM. The preparation contains supplements such as quercetin (15%), Curcuma longa root extract complex with enhanced bioavailability (BCM-95; 20%), DIM (3%), and resveratrol (0.2%). Some of these components have shown a strong doseand time-dependent growth inhibition and apoptotic death in prostate cancer cells; 25 mM of quercetin inhibited about 50% PC3 cell growth for 72 hours. At 24 hours, 50 mM and 100 mM quercetin induced G2/M arrest and apoptosis, manifested by the decrease in G2/M-related protiens.

Researchers summarise  that,    ProstaCaid has anti-cancer activities in both AD and AI prostate cancer cells at very low concentrations (25 mg/mL). It also suggests that ProstaCaid inhibits cell growth and survival, at least through the inhibition of AKT and MAPK signaling. The effect on AI cell lines is especially of importance as there is presently no curative therapy for hormone refractory prostate cancer.

Researchers postulate that ProstaCaid may affect activity of Cdc2/cyclin B1 kinase by reducing this complex formation. Cdc2 could be dephosphorylated by Cdc25C and become inactive or be phosphorylated by protein kinase, such as Wee1, and then converted into an inactive form. They also suggest that more studies are needed in the future to test it and to define its upstream events in PC3 cells.

Ref : Jun Yan and Aaron E. Katz, Integr Cancer Ther 2010 9: 186

Antimalarial drugs could find another use as cancer treatments, study says

Antimalarial drugs chloroquine and hydroxychloroquine could find another use as cancer treatments, according to a new clinical study published in ecancermedicalscience.

Researchers from the Repurposing Drugs in Oncology (ReDO) project, an international collaboration between the Anticancer Fund, Belgium, and USA-based GlobalCures, say there is evidence to include these drugs in further clinical investigations.

The authors are particularly excited about the potential for chloroquine and hydroxychloroquine as the evidence suggests they make tumor cells more sensitive to cancer treatment.
Chloroquine   Hydroxy chlroquine 

"What makes chloroquine and hydroxychloroquine so interesting is these multiple mechanisms of action", says Ciska Verbaanderd of the Anticancer Fund and the University of Leuven, Belgium, first author of the study."These antimalarial drugs act on both the level of cancer cells and the tumor microenvironment." Studying this has led to interesting scientific insights in tumor biology, such as the importance of autophagy, the tumor vasculature and the immune system."

"The results from the review lead us to believe that these antimalarial drugs could offer significant clinical benefit for certain cancer patients, especially in combination with standard anticancer treatments.This should be confirmed by additional clinical results."

Vikas P. Sukhatme MD ScD, co-founder of GlobalCures and one of the authors of this review, added "We look forward with much anticipation to the results of the 30 or so ongoing clinical studies that use chloroquine or hydroxychloroquine for cancer treatment."

The researchers' hope is that with the publication of this study, increased awareness of the potential applications will bring these medications out of the medicine cabinet - and into cancer care.

Previous papers from the ReDO project have explored how inexpensive, common drugs such as beta-blockers and anti-fungal remedies can be "repurposed" and used as part of cancer treatments.

Ref : http://ecancer.org/news/12864-antimalarial-drugs-could-support-existing-cancer-treatments-in-two-pronged-attack.php

Antimalarial drugs could find another use as cancer treatments, study says

Eribulin mesylate drug may help extend lives of women with advanced breast cancer..

We know that, Eribulin (see structure E7389) is an investigational  anticancer drug. Eribulin was previously known as E7389.  Eribulin is currently being investigated by Eisai Co. for the third-line treatment of advanced breast cancer in patients who have been previously treated with anthracyclines, taxanes and capecitabine, as well as a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.

Structurally, eribulin is a fully synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B a potent mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges. Eribulin is a mechanistically-unique inhibitor of microtubule dynamics, exerting its anticancer effects by triggering apoptosis of cancer cells following prolonged mitotic blockage. A new synthetic route to E7389 was published in 2009.

Now   research team at the University of Leeds and St James's Institute of Oncology led an international trial of the new chemotherapy drug, eribulin mesylate. As per the claim by the researchers, average survival was typically 25 per cent longer for women who took eribulin mesylate.

In the EMBRACE trial, 762 patients with advanced breast cancer received either eribulin or standard cancer treatment. All of the patients had already been heavily treated with conventional therapies, but their disease had returned or spread to other parts of the body.  Researchers concluded that those who took the new drug lived for 13.1 months, on average, compared with 10.7 months for those on conventional chemotherapy. The drug was also well-tolerated by most patients. Researchers hope that these results may establish eribulin as a new, effective treatment for women with late-stage metastatic breast cancer (either single drug or in combination with other anticancer drug). The drug is not yet available for routine clinical treatment and is awaiting regulatory approval in the European Union, the US and Japan.

"Until now, there hasn't really been a standard treatment for women with such advanced breast cancer. For those women who have already received all of the recognised treatments, these are promising results, claims the lead investigator Professor Christopher Twelves...

Ref : http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50309

Statins as anticancer and anti diabetic agents ?

We know that statins are widely used as cholesterol lowering drugs. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. But researchers from University of Gothenburg, have found that statins might be useful as anticancer and antidiabetic too.

Statins lower cholesterol by blocking certain enzymes involved in our metabolism. However, they have also been shown to affect other important lipids in the body, such as the lipids that help proteins to attach to the cell membrane (known as lipid modification). Because many of the proteins that are lipid-modified cause cancer, there are now hopes that it will be possible to use statins in the treatment of cancer.

Studies show that statins can have a dramatic inhibitory effect on growth and development. As the researchers managed to identify the enzyme involved, they can also explain how the effect arises at molecular level. Not least that they can prevent the growth of cancer cells caused by lipid-modified proteins, but also that they can be effective in the treatment of diabetes and neurological disorders such as Parkinson's. In one of my earlier blog, I have mentioned about the simvastin (Simvastatin prevents progression of Parkinson's Disease ?).

So in the days to come statins may be useful as anticancer, anti diabetic and even to treat Parkinsons disaese....


Source : http://www.science.gu.se/english/News/News_detail/Cholesterol-lowering_medicines_may_be_effective_against_cancer.cid898016

A New Approach to Faster Anticancer Drug Discovery

A new approach to drug discovery, according to scientists at the University of California, San Diego School of Medicine who used the approach to uncover a potential treatment for prostate cancer, using a drug Peruvoside (see below structure) currently marketed for congestive heart failure.  

A New Approach to Faster Anticancer Drug Discovery

Natural products isolated from marine mollusks and sponges can reverse multidrug resistance in cancer cells

Oceans are a treasure trove of naturally produced chemical compounds with impressive and varied biological activity. One class of these compounds, the lamellarins, has some members that are cytotoxic, while others are able to reverse multidrug resistance in certain cancer cells. These lamellarins (see below structure) act by inhibiting the so-called P-glycoprotein, which enhances transport of anticancer agents out of cancer cells, thus rendering the cells multidrug resistant.

Now researchers lead by Professor Rob Capon, have set out to determine the structures of a variety of lamellarins and correlate them to the activity of the compounds. As they report in Chemistry—An Asian Journal, the activity is not determined by the core structure of the compounds but rather depends on the exact nature of pendant groups adorning the periphery of the molecule. Those compounds in which many hydroxy (OH) groups had been replaced with methoxy (OCH₃) were able to reverse multidrug resistance in human colon cancer cells, while those featuring a large number of hydroxy groups showed higher cytotoxic activity.

Natural products such as the lamellarins are often valued for their cytotoxic properties for use as anticancer drugs. Capon, however, comments, "Our investigation reaffirms the view that non-cytotoxic natural products can exhibit valuable biological properties that allude to both an ecological advantage and a pharmacological potential....

Ref : http://onlinelibrary.wiley.com/doi/10.1002/asia.201101049/abstract;jsessionid=D96AD6C21A9E2EAF7D966C0743768A2A.d01t03

Itraconazole drug shows potential in cancer treatment

In continuation of my update on Itraconazole

Anti-fungal drug shows promise as potential new cancer treatment.A common anti-fungal treatment has joined the ranks of drugs that may be suitable for use in treating cancer, according to research from the Repurposing Drugs in Oncology (ReDO) project published in ecancermedicalscience.  

The ReDO project is an international collaboration of anticancer researchers dedicated to promoting the cause of common medicines which may represent an untapped source of novel therapies for cancer.

In partnership with ecancer, the ReDO project is publishing a series of papers on drugs that have enough clinical evidence to be taken to clinical trials.Itraconazole is a drug used to treat a broad range of fungal infections, including skin and nail infections.

It also has a lot of potential as a new cancer treatment, according to the ReDo project.

"Itraconazole shows potential in a number of areas with high unmet patient needs, particularly in non-small cell lung cancer and possibly in some rarer malignancies," says Pan Pantziarka, PhD, member of the ReDO project and the Anticancer Fund.

Itraconazole drug shows potential in cancer treatment

Anticancer & Antiinflammatory properties of Lunasin (Soy Peptide) established ?...

We know that many researchers have tried to establish the anticancer activity of the peptide lunasin (which has been already accepted as neutraceutical agent). Now researchers from University of Illinois have come up with more interesting facts, Soy peptide often discarded in the waste streams of soy-processing plants, may have important health benefits that include fighting leukemia and blocking the inflammation that accompanies such chronic health conditions as diabetes, heart disease, and stroke.

The researchers confirmed lunasin's bioavailability in the human body by doing a third study in which men consumed 50 grams of soy protein--one soy milk shake and a serving of soy chili daily-for five days. Significant levels of the peptide in the participants' blood give us confidence that lunasin-rich soy foods can be important in providing these health benefits.

In the cancer study, de Mejia's group identified a key sequence of amino acids- arginine, glycine, and aspartic acid, (the RGD motif)--that triggered the death of leukemia cells by activating a protein called caspase-3. The scientists also verified lunasin's ability to inhibit topoisomerase 2, an enzyme that marks the development of cancer, and they were able to quantify the number of leukemia cells that were killed after treatment with lunasin in laboratory experiments.

More interesting out come of their study is lunasin's potential anti-inflammatory activity, (first time) they showed that lunasin blocked or reduced the activation of an important marker called NF-kappa-B, a link in the chain of biochemical events that cause inflammation. They also found statistically significant reductions in interleukin-1 and interleukin-6, both important players in the inflammatory process (the reduction in interleukin-6 was particularly strong). As per the claim by the group, although the high cost of obtaining lunasin from soy waste limits its use for nutritional interventions, soy flour does contain high concentrations of the peptide (depending on some genotype soy).

Its good see the diverse activities associated with Soy......

Source : http://pubs.acs.org/doi/abs/10.1021/jf803303k?prevSearch=Elvira%2Bde%2BMejia&searchHistoryKey=

Investigational drug abemaciclib shows durable clinical activity for variety of cancer types

In continuation of my  updates on palbociclib (Ibrance)  and letrozole

Bottom Line: The investigational anticancer therapeutic abemaciclib, which targets CDK4 and CDK6, showed durable clinical activity when given as continuous single-agent therapy to patients with a variety of cancer types, including breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, and melanoma, according to results from a phase I clinical trial.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Senior authors: Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas, and Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute in Boston.

Background: In February 2015, the U.S. Food and Drug Administration (FDA) approved the CDK4/6 inhibitor palbociclib (Ibrance) for use in combination with the aromatase inhibitor letrozole for treating postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer.

  letrozole  palbociclib

The oral CDK4/6 inhibitor abemaciclib is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity, according to Shapiro. For example, abemaciclib has greater selectivity for CDK4 compared with palbociclib, which may explain why it does not affect white blood cell counts as severely, allowing it to be taken on a continuous schedule without treatment holidays, he said. Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors, he added.

 abemaciclib

How the Study Was Conducted and Results: Patnaik, Shapiro, and colleagues enrolled 225 patients with a variety of types of advanced cancer in the phase I clinical trial designed to evaluate the safety and preliminary efficacy of abemaciclib. In the dose escalation phase, the researchers determined that the maximum tolerated dose was 200 milligrams (mg) every 12 hours; the dose-limiting toxicity was grade 3 fatigue.

In the expansion phase, single-agent abemaciclib was administered to 47 patients with breast cancer, 68 with NSCLC, 17 with glioblastoma, 26 with melanoma, and 15 with colorectal cancer. Among these patients, the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts.

Radiographic responses were observed for some patients with breast cancer, NSCLC, and melanoma. Among the 36 patients with hormone receptor-positive breast cancer, 11 had a partial response, with four of the 11 responders having continued prior endocrine therapy, and an additional 18 patients had stable disease. Among the 68 patients with NSCLC, two had a partial response and 31 had stable disease; one patient who had a partial response and 12 who had stable disease were known to have KRAS-mutant NSCLC. Among the 26 patients with melanoma, one had a partial response and six had stable disease. Three of the 17 patients with glioblastoma had stable disease, with two of them continuing to receive treatment without disease progression for 19 and 23 cycles, respectively.

Author Comment: "These data show that abemaciclib is an oral drug that can be taken on a continuous schedule and achieve durable clinical activity against multiple tumors including breast and lung cancers," said Shapiro.

"The results of the trial supported the FDA decision to grant breakthrough therapy designation to abemaciclib (previously known as LY2835219) for patients with refractory hormone receptor-positive advanced or metastatic breast cancer," added Patnaik.

Limitations: Patnaik explained that because this study included 225 patients with different types of cancer, confirmatory clinical trials in specific patient populations are necessary to precisely define the role of abemaciclib in cancer care. Multiple clinical trials have already been initiated to evaluate abemaciclib as a treatment for certain groups of patients with breast cancer and NSCLC, as well as children with primary brain tumors and adults with brain metastases, she noted.

Cisplatin doubles lung cancer survival time in mice !

When I was studying my M.Sc., (1992), we used to have a question regarding the anticancer activity of cisplatin and after that I could see lots of research in the field of anticancer activity. And so many new drugs have been established and are being used as drugs. Cisplatin works by crosslinking across DNA inter-strands, making it impossible for rapidly dividing cells to duplicate their DNA for cell division (mitosis). The damaged DNA sets off DNA repair mechanisms which fails to work, so in turn activate cell death processes (apoptosis). The trans isomer does not have this pharmacological effect.

After so many years, I could find this something interesting findings about cisplatin, by Patrizia Russo of Lung Cancer Unit of the National Cancer Research Institute in Genoa, Italy and colleagues from San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Catholic University.

In the study, the authors took the research a step further and showed that α-CbT could inhibit non-small cell lung carcinoma (NSCLC) growth and prolong life in non-obese/severe combined immunodeficient (NOD/SCID) mice that had human NSCLC grafted to their lungs. This study attempted to mimic human cancer conditions more closely by delaying treatment until the tumors were well-established. In addition to control mice that were untreated, the researchers randomized one third of the mice to receive standard chemotherapy.

They found that NOD/SCID mice treated with the standard chemotherapy agent, cisplatin, had a 16 percent longer median survival time than untreated mice (p= 0.05). Mice treated with α-CbT, however, had an increased median survival time of 1.7-fold over the cisplatin-treated mice and 2.1-fold over the no-treatment controls (p=0.0005). Though the clinical trials to establish the claim and to to explore the widest range of possibilities of intervention on the α7-nAChRs. Congrats...

Ref :Inhibition of Nonneuronal 7-Nicotinic Receptor for Lung Cancer Treatment; Am. J. Respir. Crit. Care Med., Jun 2009; 179: 1141 - 1150

New drug candidate shows promise against cancer - MIT Media Relations

Drugs containing platinum are among the most powerful and widely used cancer drugs. However, such drugs have toxic side effects, and cancer cells can eventually become resistant to them. Stephen J Lippard, Chemistry Professor, MIT who has spent much of his career studying platinum drugs, has now identified a compound that kills cancer cells better than cisplatin, the most commonly used platinum anticancer drug. The new compound may be able to evade cancer-cell resistance to conventional platinum compounds.

“I’ve long believed that there’s something special about platinum and its ability to treat cancer. Using new variants, we might have a chance of applying platinum to a broader range of cancer types, more successfully,” said Lippard. Lippard is senior author of a paper describing the new drug candidate, known as phenanthriplatin - which is cis-[Pt(NH₃)₂(phenanthridine)Cl]NO_3.

New anticancer compound discovered

A team of research scientists from VTT Technical Research Centre of Finland, the University of Turku and the University of Eastern Finland has discovered a previously unknown Cent-1 molecule that kills cancer cells. Their research also shows that new cancer drug candidates can be identified faster and at lower cost by using computer-assisted and cell-based screening of compounds.

Ref: http://mct.aacrjournals.org/content/13/5/1054

New anticancer compound discovered 

How Dietary Supplement (Broccoli, Cabbage) May Block Cancer Cells....

In continuation of  how dietary supplement may block cancer cells... In my earlier blogs,  I have mentioned that, natural compound formed during the autolytic breakdown of glucobrassicin present in food plants of the Brassica genus, including broccoli, cabbage, Brussels sprouts, cauliflower and kale) are responsible for the anticancer activity associated with broccoli and other Brassica genus.

Now researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) have discovered how a substance  (see below structure) that is produced when eating broccoli and Brussels sprouts can block the proliferation of cancer cells.

Compelling evidence indicates that the substance, indole-3-carbinol [(above structure, I3C) : Glucobrassicin (right structure) is a type of glucosinolate that can be found in almost all cruciferous plants, such as cabbages  and broccoli, degradation by the enzyme myrosinase is expected to produce an isothiocyanate, indol-3-ylmethylisothiocyanate- which is unstable and hydrlyses to give, I3C, as most dominant degradation product], may have anticancer effects and other health benefits, the researchers say. These findings show how I3C affects cancer cells and normal cells.

The laboratory and animal study discovered a connection between I3C and a molecule called Cdc25A, which is essential for cell division and proliferation. The research showed that I3C causes the destruction of that molecule and thereby blocks the growth of breast cancer cells.

"Cdc25A is present at abnormally high levels in about half of breast cancer cases, and it is associated with a poor prognosis," says study leader Xianghong Zou, assistant professor of pathology at the Ohio State University Medical Center.

For this study, Zou and his colleagues exposed three breast cancer cell lines to I3C. These experiments revealed that the substance caused the destruction of Cdc25A. They also pinpointed a specific location on that molecule that made it susceptible to I3C, showing that if that location is altered (because of a gene mutation), I3C no longer causes the molecule's destruction.

Last, the investigators tested the effectiveness of I3C in breast tumors in a mouse model. When the substance was given orally to the mice, it reduced tumor size by up to 65 percent. They also showed that I3C had no affect on breast-cell tumors in which the Cdc25A molecule had a mutation in that key location.

Ref :  American Association for Cancer Research : Cancer Prevention Research, Xianghong Zou et al.,

Celastrol Inhibiting Hsp90 Chaperoning - a new way to treat cancer?

Celastrol, derived from trees and shrubs called celastracaea,  (Thunder of God Vine) has been used for centuries in China to treat symptoms such as fever, chills, joint pain and inflammation.Celastrol has been shown to possess antioxidant, anti-inflammatory activities. The same compound has been tried for Alzheimer's disease and anticancer activity  also.

Now Dr. Ahmed Chadli, has come up with an interesting findings i.e., Celastrol may play a role in cancer treatment by inactivating a protein required for cancer growth.  Protein, P23, is one of many proteins helping the heat shock protein 90. Dr. Chadli claims that,  "scientists are just beginning to realize the potential of controlling inflammation-related diseases, including cancer, by inhibiting HSP90".

As per  claim by Dr. Chadli, cancer cells need HSP90 more than normal cells because cancer cells have thousands of mutations. They need chaperones all the time to keep their mutated proteins active. By taking heat shock proteins away from cells, the stabilization is taken away and cell death occurs. 

Most HSP90 inhibitors lack selectivity, disabling the functions of all proteins activated by HSP90 rather than only the ones implicated in a specific tumor and proteins vary from one tumor to another. Dr. Chadli and colleagues at the Mayo Clinic believe celastrol holds the key to specificity, targeting the HSP90-activated protein required for folding steroid receptors.

Celastrol inhibits the Hsp90 chaperoning machinery by inactivating the co-chaperone p23, resulting in a more selective destabilization of steroid receptors compared with kinase clients. Both in vitro and in vivo results demonstrate that celastrol disrupts p23 function by altering its three-dimensional structure, leading to rapid formation of amyloid-like fibrils. This study reveals a unique inhibition mechanism of p23 by a small molecule that could be exploited in the dissection of protein fibrillization processes as well as in the therapeutics of steroid receptor-dependent diseases....

Ref : http://www.jbc.org/content/285/6/4224.abstract

Antidepressant, TCP (Trabylcypromine) could help the workings of anticancer drug used in leukemia...

A new study shows that an antidepressant could be crucial in helping cancer treatment drugs reach their full potential.

The study by scientists at the Institute of Cancer Research found that tranylcypromine (TCP - cis and trans iosmers - below structures) – which can be used to treat psychotic depressive states - can make cancer cells vulnerable to the effects of a vitamin A- derivative drug called ATRA (above structure).

Retinoids are a class of chemical compounds related chemically to vitamin A. ATRA is already used successfully to treat a rare form of acute myeloid leukemia (AML), but up until now, has not been effective against other types of the disease. ATRA works by encouraging leukemia cells to mature and die naturally, but the researchers lead by Ar. Arthur Zelent say that the reason many AML patients do not respond to the treatment is because the genes that ATRA normally attacks are switched off by an enzyme called LSD1. The scientists discovered that using TCP to block this 'off switch' could reactivate these genes, making the cancer cells susceptible to ATRA.

The team has already joined forces with the University of Munster in Germany to start a Phase II clinical trial of the drug combination in AML patients. The authors also commented that both the retinoid ATRA and the antidepressant TCP are already available in the UK and off-patent, so these drugs should not be expensive for the health service. 

Ref : http://www.icr.ac.uk/research/new_research_highlights/research_highlights/22625.shtml

Cornerstone's CPI-613 drug candidate chosen as 2014 Top 10 Most Interesting Oncology Projects to Watch

We know that, CPI-613: CPI-613  is a racemic mixture of the enantiomers of a synthetic alpha-lipoic lipoic acid analogue with potential chemopreventive and antineoplastic activities. Although the exact mechanism of action is unknown, alpha-lipoic acid analogue CPI-613 has been shown to inhibit metabolic and regulatory processes required for cell growth in solid tumors. Both enantiomers in the racemic mixture exhibit antineoplastic activity. The mechanism-of-action of CPI-613 appears distinct from the current classes of anti-cancer agents used in the clinic. CPI-613 demonstrates both in vitro and in vivo anti-tumor activity.CPI-613 was known to strongly disrupt tumor mitochondrial metabolism. CPI-613 disruption of tumor mitochondrial metabolism is followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines. Further, CPI-613 shows strong antitumor activity in vivo against human non-small cell lung and pancreatic cancers in xenograft models with low side-effect toxicity. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus). (last updated: 10/30/2014)

Now...........

Cornerstone Pharmaceuticals, Inc., a development stage company and leader in the growing field of cancer metabolism-based therapeutics, today announced that its lead compound CPI-613 has been chosen by Informa and Kantar Health as one of the 2014 Top 10 Most Interesting Oncology Projects to Watch.

Steve Carchedi, Chief Executive Officer of Cornerstone Pharmaceuticals, will present at Informa’s Therapeutic Area Partnerships meeting, taking place November 19-21, 2014 at the Hyatt Regency in Boston. Mr. Carchedi’s presentation will occur at 11:00 a.m. on November 20 within Track 3 (Oncology).

During the presentation, Mr. Carchedi will discuss differentiators of Cornerstone’s lead Altered Energy Metabolism Directed (AEMD) drug candidate, CPI-613, which is a first-in-class anticancer compound designed to disrupt the altered energy-production pathways in cancer cells by targeting mitochondrial metabolism.

Cornerstone's CPI-613 drug candidate chosen as 2014 Top 10 Most Interesting Oncology Projects to Watch

Lovastatin-synthesizing enzyme successfully reconstituted...

Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms and red yeast rice. When I was working with a Banglore based company (Biocon), they did try this compound and I think the company is marketing this drug now. As for as my knowledge goes there were two ways to synthesise 'biosynthesis using Dield-Alder catalyzed cyclization' & 'biosyntheis using broadly specific acyltransferase'

Dield-Alder catalysed cyclisation : In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. The stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.

Biosynthesis using broadly specific acyltransferase : It has been found that a dedicated acyltransferase, LovD, is encoded in the lovastatin biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J. The biosynthesis of lovastatin is coordinated by two iterative type I polyketide syntheses and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of lovastatin, is assembled by the upstream megasynthase LovB (also known as lovastatin nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases.

Recently more interesting out come from a group of UCLA researchers is that, for the first time thy have successfully reconstituted in the laboratory the enzyme responsible for producing the blockbuster cholesterol-lowering drug lovastatin. As per the claim by the researchers, the lovastatin-synthesizing enzyme is one of the most interesting but least understood of the polyketide synthases, which are found in filamentous fungi and which play a crucial role in the synthesis of "small molecule natural products" — pharmacologically or biologically potent compounds produced by living organisms, many of which are the active ingredients in pharmaceuticals.

This finding is of great significance because commonly used antibiotics, such as tetracycline, are produced by polyketide synthases. Polyketides represent a class of 7,000 known structures, of which more than 20 are commercial drugs, including the immunosuppressant rapamycin, the antibiotic erythromycin and the anticancer drug doxorubicin. In their study studied the enzyme that makes a small-molecule precursor to lovastatin. The real difference about this enzyme, is its extraoridnarily large size in comparison to all other enzymes so for studied. As per the claim by the lead researcher Dr. Yi Tang, "It's one of the largest enzymes ever to be reconstituted in a test tube. It is 10 times the size of most enzymes people study & the enzyme has seven active sites and catalyzes more than 40 different reactions that eventually result in an important precursor to lovastatin. Hope with this remarkable achievement, one can prepare many natural products in the lab in the days to come.

Ref : http://www.newsroom.ucla.edu/portal/ucla/ucla-engineering-researchers-have-111812.aspx