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

Triphase's marizomib receives FDA orphan drug designation for treatment of multiple myeloma

Salinosporamide A (Marizomib) is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery. This novel marine natural product is produced by the recently described obligate marine bacteria Salinispora tropica and Salinispora arenicola, which are found in ocean sediment. Salinosporamide A belongs to a family of compounds, known collectively as salinosporamides, which possess a densely functionalized γ-lactam-β-lactone bicyclic core.

Triphase Accelerator Corporation recentlyannounced that marizomib, its novel, potent proteasome inhibitor, has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA)'s Office of Orphan Products Development for the treatment of multiple myeloma. The orphan drug designation will provide Triphase with 7-year marketing exclusivity for marizomib and other benefits upon FDA approval.

"We are pleased that the FDA has granted orphan drug designation for the development of marizomib to benefit patients with multiple myeloma," said Frank Stonebanks, founder, president and CEO of Triphase. "While patients with refractory multiple myeloma are living longer and better lives as a result of medical innovation, there is still a need for new treatment options. We are excited to move forward with the development of marizomib, a potential best-in-class agent, and hope to advance the treatment paradigm that will turn this once acute disease into a long-term manageable disease."

Triphase's marizomib receives FDA orphan drug designation for treatment of multiple myeloma

Old FDA-approved drugs may hold promise for treatment of rare, drug-resistant cancer

After studying how samples of GIST responded to various concentrations of the 89 drugs in the laboratory, Dr. Duensing and her colleagues identified 37 compounds that showed some anticancer activity in at least one of the concentrations tested. Importantly, they noted that the most promising candidates all belonged to only two major drug classes: inhibitors of gene transcription and so-called topoisomerase II inhibitors. Based on these findings, the research team selected the two most promising compounds for further testing - gene transcription inhibitor mithramycin A (left structure below) , which is in clinical trials to treat Ewing sarcoma, and topoisomerase II inhibitor mitoxantrone (beow right structure), which is used in metastatic breast cancer and leukemia.

Both drugs were highly effective in fighting GIST in laboratory tests. Moreover, the mechanism of action of each drug was linked to the specific underlying biology of these tumors.

"These are very encouraging results," said Dr. Duensing. "The next step will be moving our findings to clinical exploration to see if the results we found in the lab hold up in patients."

Old FDA-approved drugs may hold promise for treatment of rare, drug-resistant cancer

Ref : http://www.upmc.com/media/NewsReleases/2014/Pages/upci-scientists-detect-therapy-for-drug-resistant-cancer.aspx

Biotechdaily - Nilotinib Enhances Toxic Protein Removal from Parkinson's Disease Neurons

In continuation of my update on Nilotinib

The anticancer drug nilotinib induces clearance of the toxic protein alpha-synuclein from   neurons in a mouse model of Parkinson's disease and ameliorates symptoms of the disease.

Investigators at Georgetown University Medical Center (Washington DC, USA) worked with a mouse model of Parkinson’s disease. They reported in the May 10, 2013, online edition of the journal Human Molecular Genetics that lentiviral transfection of the gene encoding alpha-synuclein into the mouse SN lead to activation (phosphorylation) of the tyrosine kinase Abl and that lentiviral transfection of the gene encoding Abl increased alpha-synuclein levels, which exacerbated the disease. Administration of the tyrosine-kinase inhibitor nilotinib decreased Abl activity and increased autophagic clearance of alpha-synuclein into lysosomes in transgenic and lentiviral gene-transfer models.

The drug nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In 2006, a Phase I clinical trial found that nilotinib had a relatively favorable safety profile and showed activity in cases of CML resistant to treatment with imatinib (Gleevec [USA]/ Glivec [Europe, Australia, and Latin America]), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study, 92% of patients (already resistant or unresponsive to imatinib) achieved a normal white blood cell counts after five months of treatment.

In the current study, nilotinib, which enters the brain within [US] Food and Drug Administration approved doses, led to autophagic degradation of alpha-synuclein, protection of SN neurons and improvement of motor performance in the Parkinson’s disease mice.

 
"No one has tried anything like this before," said senior author Dr. Charbel E-H Moussa, assistant professor of neuroscience at the Georgetown University Medical Center. "This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain."

"The doses used to treat CML are high enough that the drug pushes cells to chew up their own internal organelles, causing self-cannibalization and cell death," said Dr. Moussa. "We reasoned that small doses—for these mice, an equivalent to 1% of the dose used in humans—would turn on just enough autophagy in neurons that the cells would clear malfunctioning proteins, and nothing else. We successfully tested this for several diseases models that have an accumulation of intracellular protein. It gets rid of alpha-synuclein and tau in a number of movement disorders, such as Parkinson's disease as well as Lewy body dementia."

Biotechdaily - Nilotinib Enhances Toxic Protein Removal from Parkinson's Disease Neurons

Peptide derived from cow's milk kills human stomach cancer cells in culture

New research from a team of researchers in Taiwan indicates that a peptide fragment derived from cow's milk, known as lactoferricin B25 (LFcinB25), exhibited potent anticancer capability against human stomach cancer cell cultures. The findings, published in the Journal of Dairy Science^®, provide support for future use of LFcinB25 as a potential therapeutic agent for gastric cancer.

"Gastric cancer is one of the most common causes of cancer-related mortality worldwide, especially in Asian countries," says Wei-Jung Chen, PhD, of the Department of Biotechnology and Animal Science of National Ilan University, Taiwan Republic of China. "In general, the main curative therapies for gastric cancer are surgery and chemotherapy, which are generally only successful if the cancer is diagnosed at an early stage. Novel treatment strategies to improve prognosis are urgently needed."

Investigators evaluated the effects of three peptide fragments derived from lactoferricin B, a peptide in milk that has antimicrobial properties. Only one of the fragments, LFcinB25 reduced the survival of human AGS (Gastric Adenocarcinoma) cells in a dose-dependent and time-dependent manner.

Under a microscope the investigators could see that after an hour of exposure to the gastric cancer cells, LFcinB25 migrated to the cell membrane of the AGS cells, and within 24 hours the cancer cells had shrunken in size and lost their ability to adhere to surfaces. In the early stages of exposure, LFcinB25 reduced cell viability through both apoptosis (programmed cell death) and autophagy (degradation and recycling of obsolete or damaged cell parts). At later stages, apoptosis appeared to dominate, possibly through caspase-dependent mechanisms, and autophagy waned.

"This is the first report describing interplay between apoptosis and autophagy in LFcinB-induced cell death of cancer cells," says Dr. Chen.

Ref : http://www.journalofdairyscience.org/article/S0022-0302(13)00722-4/abstract

Peptide derived from cow's milk kills human stomach cancer cells in culture

Toxicity limits benefits of bevacizumab–erlotinib NSCLC maintenance therapy

In continuation of my update on bevacizumab and erlotinib 

Two targeted anticancer drugs used together after first-line chemotherapy for advanced stage non-small-cell lung cancer (NSCLC) improve progression-free survival (PFS), the results of a large, prospective study show.

Median PFS was 4.8 months for patients treated with bevacizumab plus erlotinib versus 3.7 months for those treated with bevacizumab plus placebo (hazard ratio [HR] = 0.71). There was no overall survival (OS) advantage, however, and the two-drug combination was associated with more adverse events than bevacizumab alone, say the study investigators.

Toxicity limits benefits of bevacizumab–erlotinib NSCLC maintenance therapy

New Cancer Targeting Technique to Improve Cancer Drugs

Cancer drugs work because they’re toxic, but that’s also why they afflict healthy cells, producing side effects that can compromise their efficacy. Nobuhide Ueki thinks he may have found a way to get the drugs to selectively target only the cancer cells, and his team’s patent-pending research is the subject of a paper entitled “Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease,” 

Authors demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysinegroup to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.

Read : Nature Communications

New Cancer Targeting Technique to Improve Cancer Drugs

New drug candidate found for deadly fungal lung infections

Rappleye's team searched a library of commercially-available small molecules used by other investigators to find new antivirals or anticancer drugs. They performed a high-throughput phenotypic screen of 3,600 compounds looking for agents that inhibited fungal, but not human, cells.

To speed the selection process, Rappleye and Edwards engineered Histoplasma cells with a fluorescent protein that made the cells glow red while inside of a living macrophage -- the type of mammalian immune cell that Histoplasma attacks and in which it reproduces.

As the number of fungal cells increased inside the macrophage, so did the fluorescence and consequently, the cells would glow brighter. However, when a macrophage was exposed to an active compound that prevents Histoplasma reproduction, it maintained the same level of brightness. This allowed the scientists to quickly determine efficacy and toxicity of the drug candidate in a natural environment.

"Not only were we able to visually screen thousands of compounds in just a few weeks, but we were also able to measure the compound's impact in a real, live host cell," said Edwards.

The team narrowed down to a primary candidate called 41F5, which is 60 times more toxic to fungal cells than human cells. Their work was published in the September Antimicrobial Agents and Chemotherapy.

The team is currently working with Werner Tjarks, PhD, a medicinal chemist at Ohio State, to see if the selectivity and toxicity profile can be enhanced further for additional testing. Rappleye is also working with the Ohio State's Technology Commercialization Office (TCO) to potentially commercialize the derivatives from 41F5.

Ref : http://aac.asm.org/content/57/9/4349.abstract?sid=3bdf09cf-45fe-47e2-ad56-66b4ef40ae7e

New drug candidate found for deadly fungal lung infections

New class of highly potent antimalarial compounds discovered

In a recent work published online today in the journal PNAS, researchers at the Instituto de Medicina Molecular (IMM), in Lisbon, Portugal, have discovered a new class of highly potent antimalarial compounds. These compounds, referred to as Torins, were originally developed by researchers in the Boston, MA to inhibit a key human protein involved in cell growth, mTOR, and have been shown to be effective anticancer agents in rodent models. In research perdormed by Dr. Kirsten Hanson in the laboratory of Dr. Maria Mota, the IMM team and their collaborators have discovered that Torins are extremely effective multistage antimalarials; Torins appear to have a novel activity against the Plasmodium parasites themselves, distinct from both currently used malaria therapeutics and from their ability to target human mTOR.

Torins are capable of killing the cultured blood stages of the human parasite, Plasmodium falciparum, the species which causes most malaria deaths and severe disease, and are equally potent against the liver stages of a model rodent parasite. A single dose of the compound Torin2 delivered at the beginning of the P. berghei liver stage is sufficient to eliminate infection in mice before any Plasmodium parasites reach the blood. "Given the alarming trend of resistance to our current antimalarial therapies, this is really an exciting finding," says Dr. Mota, the senior author of the study, "and we are already working to develop Torin molecules suitable for clinical trials of antimalarial activity in humans."

 Ref : http://www.pnas.org/content/early/2013/07/03/1306097110.full.pdf+html

New class of highly potent antimalarial compounds discovered

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'

Diabetes drug points the way to overcoming drug resistance in melanoma

Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. Researchers  identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B^high subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.

Ref: http://www.cell.com/cancer-cell/retrieve/pii/S1535610813001967 

Diabetes drug points the way to overcoming drug resistance in melanoma

p53 activation suppresses malic enzyme expression and leads to senescence in pre-cancerous cells

A team of researchers from the Perelman School of Medicine, University of Pennsylvania, has identified a class of p53 target genes and regulatory molecules that represent more promising therapeutic candidates. Researchers describes that, p53 participates in a molecular feedback circuit with malic enzymes, thereby showing that p53 activity is also involved in regulating metabolism.(The Yang lab identified p53's role in glucose metabolism in the past.)

The new findings, Yang  (lead researcher) says, suggest that p53 acts as a molecular sensor of metabolic stress and explains how metabolic stress can lead to senescence in cells.

"We uncovered an important regulatory mechanism for p53 as well as an effector mechanism for p53," Yang says.

Significantly, the findings also identify malic enzymes as novel and potentially useful pharmaceutical targets for anticancer therapy, as well as possible mediators of the normal aging process   though neither possibility was actually addressed in the current study.

As cells become damaged and precancerous, the p53 protein prevents those cells from continuing towards becoming tumors by causing the cells to senesce. Metabolic cues also regulate senescence, but the molecular relays coupling those two processes,  senescence and metabolism  remained unknown................

p53 activation suppresses malic enzyme expression and leads to senescence in pre-cancerous cells

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.

Drug kills cancer cells by restoring faulty tumor suppressor

A new study describes a compound that selectively kills cancer cells by restoring the structure and function of one of the most commonly mutated proteins in human cancer, the "tumor suppressor" p53. The research, published by Cell Press in the May 15th issue of the journal Cancer Cell, uses a novel, computer based strategy to identify potential anti-cancer drugs, including one that targets the third most common p53 mutation in human cancer, p53-R175H. 

Restoring the function of mutant p53 with a drug has long been recognized as an attractive cancer therapeutic strategy," explains senior study author, Dr. Darren R. Carpizo, from The Cancer Institute of New Jersey. "However, it has proven difficult to find compounds that restore the lost function of a defective tumor-suppressor."

Using the National Cancer Institute's anticancer drug screen data researchers identified two compounds from the thiosemicarbazone family that manifest increased growth inhibitory activity in mutant p53 cells, particularly for the p53^R175 mutant. Mechanistic studies reveal that NSC319726 (see structure) restores WT structure and function to the p53^R175 mutant. 

This compound kills p53^R172H knockin mice with extensive apoptosis and inhibits xenograft tumor growth in a 175-allele-specific mutant p53-dependent manner. This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53^R175 mutant reactivator and as a lead compound for p53-targeted drug development.

Drug kills cancer cells by restoring faulty tumor suppressor

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

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

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

Discovery of a Biochemical Basis for Broccoli's Cancer-Fighting Ability

In continuation of my update on broccoli and its anticancer activity.....

Fung-Lung Chung and colleagues showed in previous experiments that substances called isothiocyanates (or ITCs)  found in broccoli, cauliflower, watercress, and other cruciferous vegetables appear to stop the growth of cancer. But nobody knew exactly how these substances work, a key to developing improved strategies for fighting cancer in humans. The tumor suppressor gene p53 appears to play a key role in keeping cells healthy and preventing them from starting the abnormal growth that is a hallmark of cancer. When mutated, p53 does not offer that protection, and those mutations occur in half of all human cancers. ITCs might work by targeting this gene, the report suggests.

Scientists studied the effects of certain naturally-occurring ITCs on a variety of cancer cells, including lung, breast and colon cancer, with and without the defective tumor suppressor gene. They found that ITCs are capable of removing the defective p53 protein but apparently leave the normal one alone. Drugs based on natural or custom-engineered ITCs could improve the effectiveness of current cancer treatments or lead to new strategies for treating and preventing cancer.

Ref : http://pubs.acs.org/doi/abs/10.1021/jm101199t

Mouse study finds black raspberries can prevent colorectal cancer

We know that, The blackberries, as well as various other Rubus species with mounding or rambling growth habits, are often called brambles. However, this name is not used for those like the raspberry that grow as upright canes, or for trailing or prostrate species such as most dewberries, or various low-growing boreal, arctic, or alpine species. Black raspberries have been also reported to possess antioxidant, anti-cancer, anti-neurodegenerative and anti-inflammatory properties, now the researchers from UIC College of Medicine have looked at the fruit's ability to prevent colon cancer.

The researchers used two strains of mice, Apc1638 and Muc2, which each have a specific gene knocked out, causing the mice to develop either intestinal tumors (in the case of Apc1638) or colitis in the case of Muc2. Colitis is an inflammation of the large intestine that can contribute to the development of colorectal cancer.

Both mouse strains were randomized to be fed either a Western-style, high-risk diet (high in fat and low in calcium and vitamin D) or the same diet supplemented with 10 percent freeze-dried black raspberry powder for 12 weeks.

The researchers found that in both mouse strains the black raspberry-supplemented diet produced a broad range of protective effects in the intestine, colon and rectum and inhibited tumor formation.

In the Apc1638 mice, tumor incidence was reduced by 45 percent and the number of tumors by 60 percent. The researchers found that black raspberries inhibited tumor development by suppressing a protein, known as beta-catenin, which binds to the APC gene.

In the Muc2 mice, tumor incidence and the number of tumors were both reduced by 50 percent, and black raspberries inhibited tumor development by reducing chronic inflammation associated with colitis.

The researchers now hope to obtain funding to begin clinical trials in humans. Because black raspberries not only prevent cancer but also inflammation, they may also protect against other diseases, such as heart disease.

I read an article in the same lines, wherein the researchers attribute the colorectal anticancer activity due to the anthocyanins present

More...