Saturday, June 16, 2018

New drug reduces symptoms of Rett syndrome in preclinical models

A new article published in the Cell Reports describes how a new drug is able to reduce the symptoms and activate the dormant neurons characteristic of Rett Syndrome in preclinical models. The study, led by Dr. Manel Esteller, Director of the Epigenetics and Cancer Biology Program (PEBC) of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA Researcher and Professor of Genetics of the University of Barcelona, and Dr. Sonia Guil, researcher at the same IDIBELL group, has been possible thanks to the support from the Catalan and Spanish associations of the Rett Syndrome, the Carla Regatta, a Verkami crowfunding campaign, the Jérôme Leujene Foundation and the Dischrom project funded by EU.

Rett Syndrome is the second most frequent cause of intellectual disability in women, only after Down Syndrome. The main genetic cause of Rett Syndrome is the appearance of mutations in the embryo affecting the MECP2 gene, a regulator of the expression of other genes in the genome. There is no specific pharmacological treatment for the disease, so current efforts are focused on trying to control its most serious manifestations, such as epileptic and respiratory crises.
"We knew for some years that the brains of Rett syndrome girls were inflamed, so we decided to test whether a drug that inhibits a central neuroinflammatory protein called glycogen synthase kinase-3B (GSK3B) could reverse part of the symptoms. As with any experimental treatment, we started with a preclinical model of the disease, studying it in mice that have the same MECP2 deficiency as in human Rett syndrome" says Dr. Manel Esteller.
SB216763 Chemical Structure
"The results have been very promising; agent SB216763 has been able to lengthen the life of the animals, significantly reducing tremors, breathing difficulties and mobility limitations. But what is really remarkable is that the inhibition of GSK3B also causes an "awakening" of the sleeping neurons of the syndrome: these brain cells are now beginning to regain contact between them and communication between neuronal synapses increases", explains the IDIBELL researcher, and he concludes: "Our findings provide a new way of improving the quality of life of these patients and now it is the neurologists' job to demonstrate their applicability in patients with Rett Syndrome. In any case, we have to be aware that the mutation in the MECP2 gene is still there, and only by correcting it would we arrive at a definitive treatment of the disease."
Ref : http://www.idibell.cat/modul/news/en/1076/a-new-drug-shows-preclinical-efficacy-in-rett-syndrome

Wednesday, June 13, 2018

FDA Approves Supplemental New Drug Application for Myrbetriq (mirabegron) for Use in Combination with Solifenacin Succinate for the Treatment of Overactive Bladder Symptoms



In continuation of my update on mirabegron

Astellas Pharma Inc. announced  that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for the use of mirabegron in combination with the muscarinic antagonist solifenacin succinate for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and urinary frequency.




Mirabegron.svg


In the United States, mirabegron and solifenacin succinate are marketed as Myrbetriq® and VESIcare®, respectively. Each is approved by the FDA as a monotherapy for OAB. 
"OAB patients may have symptoms that are not fully managed with their current treatment," said Carol Schermer, M.D., M.P.H., senior medical director, urology, Astellas. "With the FDA approval of Myrbetriq in combination with solifenacin succinate, Astellas is able to offer an additional treatment option to individuals living with symptoms of OAB."
The sNDA submission was based on data from the global Phase 3 SYNERGY I, SYNERGY II and BESIDE studies. These studies evaluated combination therapy with mirabegron and solifenacin succinate compared with each drug as monotherapy or placebo.

Tuesday, June 12, 2018

Mepivacaine is found to be an effective spinal anesthetic for knee replacement surgery

A numbing medicine largely abandoned decades ago for pain control during surgery could be making a comeback as an effective spinal anesthetic for today's modern-day knee replacement.
In two companion studies by Henry Ford Health System, mepivacaine was found to be as effective for controlling pain with less side effects as bupivacaine, which for years has been the standard spinal anesthetic favored by anesthesiologists and orthopedic surgeons. Patients who received mepivacaine recovered normal function faster, which allowed for a quicker recovery and shorter hospital stay.
Mepivacaine.png
While the results proved promising, researchers say more research is needed to evaluate mepivacaine's effectiveness on a larger scale for medium length surgery. The findings – one study was published recently in The Journal of Arthroplasty – add to a growing body of research involving similar shorter acting medications with improved results.
"Our studies suggests that mepivacaine has multiple advantages and few drawbacks compared to bupivacaine as a spinal anesthetic in knee replacement surgery," says Jason Davis, M.D., a Henry Ford joint replacement surgeon and the study's senior author. "It shows promise as an ideal anesthetic by working long enough for most knee replacements without the excessive duration that can delay patients' recovery."
As the popularity of bupivacaine was established in the 1990s, mepivacaine use became limited after research showed it had a higher incidence of post-surgery complications like nerve irritation. More recent studies have refuted those previous concerns and shown improved side effects, while allowing for a faster return of nerve function.
Total knee replacement is one of the most commonly performed orthopedic procedures. It's estimated that the number of knee replacements is expected to increase by nearly 700 percent by 2030 as the population ages. Recent studies show up to 25 percent or more of these patients may benefit from a partial knee replacement, an alternative to total knee replacement, making the potential for outpatient surgery even more feasible.
During a knee replacement procedure, the surgeon replaces the damaged joint surface with a knee implant to restore the alignment and function of the knee. More than 90 percent of knee replacements are functioning 15 years and more after surgery, according to the American Academy of Orthopaedic Surgeons.
In the Henry Ford studies, researchers sought to evaluate the safety and effectiveness of mepivacaine compared to bupivacaine as a spinal anesthetic for pain control during surgery. One involved a retrospective review of the clinical results of 156 knee replacement patients. The second involved a smaller randomized study of 32 patients that looked specifically at the timing of nerve recovery in the legs and for urinary control.
In both, Dr. Davis noted patients who received mepivacaine had better urinary control, faster recovery of nerve function and accelerated recovery compared to those who received bupivacaine. Patients fared no worse with other side effects like nerve complications, pain control or nausea.
"Advances in surgical technique and pain control have made for improved early outcomes in recent years," Dr. Davis says. "Choosing the right anesthetic may now be the key to attain a faster recovery with a lower risk of complications after surgery. Such shorter acting medications have the potential to become the new standard for regional anesthesia during the migration to outpatient joint replacement."
Ref: https://www.henryford.com/news/2018/05/knee-replacement-study

Saturday, June 9, 2018

FDA Approves Tafinlar + Mekinist for the Treatment of BRAF-Positive Anaplastic Thyroid Cancer

In continuation of my update on Tafinlar (dabrafenib) and Mekinist (trametinib)

The U.S. Food and Drug Administration approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive).

Dabrafenib.svg  dabrafenib     Trametinib.svg trametinib

“This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.”
Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1 to 2 percent of all thyroid cancers.
Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer.
The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57 percent experienced a partial response and 4 percent experienced a complete response; in nine (64 percent) of the 14 patients with responses, there were no significant tumor growths for six months or longer.
The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea).
Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia.
Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes.
Both Tafinlar and Mekinist can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.
The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

Friday, June 8, 2018

Methylene blue could hold the key to future anti-aging treatment

In continuation of my update on Methylene Blue
In a  keynote address to the 19th World Dermatology Congress, renowned dermatologist Dr. Saad Sami AlSogair noted that the past could hold the key to the future of anti-aging.
Methylene blue-2d-skeletal.svg
Dr. AlSogair's presentation to a packed house, titled "Anti-Aging Potentials of Methylene Blue for Human Skin Longevity," provided compelling evidence of methylene blue's ability to delay aging-related mitochondrial dysfunction and stimulate collagen and elastin. Together, these factors point to an anti-aging breakthrough nearly 150 years in the making.
"Methylene blue was first synthesized in 1876 and has been in use in clinical medicine ever since," Dr. AlSogair explained. "It is a powerful antioxidant and has proven effective in treating a variety of conditions from malaria to Alzheimer's disease, with a very low risk of side effects. But, it is only recently that methylene blue has been shown to be a promising treatment for mitochondrial dysfunction, which causes a wide variety of diseases and problems, including visible aging of the skin."
Dr. AlSogair, a board-certified dermatologist from Saudi Arabia, was tapped to deliver the keynote due to his prominence in the medical community. In 2013, the World Organization of Aesthetic Medicine Doctors named Dr. AlSogair "Dermatologist of the Year" for outstanding contributions to his field. In 2015, the Swiss Academy of Cosmetic Dermatology and Aesthetic Medicine elected Dr. AlSogair as its Middle East Ambassador. And since 2016, Dr. AlSogair has served as vice president of the Middle East International Dermatology and Aesthetic Medicine Conference and Exhibition (MEIDAM).
Among Dr. AlSogair's findings: Methylene blue can delay the deterioration that was once thought to be an unavoidable sign of aging. Methylene blue has been shown to enhance cellular oxygen consumption--a key weapon in the fight against free radicals--by 37% to 70%. It is highly soluble in both water and organic solvents with a low redox potential.
In the most promising and buzz-worthy part of his keynote, Dr. AlSogair informed the crowd that methylene blue actually reverses aging, has a neuroprotective effect on Alzheimer's patients, extended the life of female mice by 6%, and showed promise in the treatment of progeria, a rare genetic disorder that causes rapid-aging in children.
What's more, when applied to a 3D skin model, methylene blue promoted wound healing, increased skin hydration, and thickened the skin to a more youthful depth. But one of the most exciting dermatological findings learned was centered on one of the most obvious--and reviled--signs of aging: Wrinkles.
"Wrinkling is a highly visible feature of aged skin, and in the dermatology field, it is one of the top reasons patients seek treatment," Dr. AlSogair explained. "Skin wrinkling in aging is due to a reduction in collagen. Upon treatment with methylene blue, however, we see an increase in collagen production and skin hydration, as well as the prevention of collagen degradation. Taken together, our findings indicate methylene blue has promise in anti-aging cosmetic formulations."
The 19th World Dermatology Congress was held in Tokyo on May 7th and 8th, 2018. Other prominent speakers were Mexico's Andrea Merino-Ruisanchez, Italy's Roberto Dell'Avanzato, and China's Yan Li.

Thursday, June 7, 2018

Phase 2 study of dexpramipexole in hypereosinophilic syndromes meets its co-primary endpoints

Knopp Biosciences LLC today announced the publication of a report in the journal Bloodthat a Phase 2 study of dexpramipexole in hypereosinophilic syndromes (HES) met its co-primary endpoints.
Dexpramipexole.png
A team of investigators led by Dr. Amy Klion at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), undertook the open-label study of dexpramipexole as a steroid-sparing agent in subjects with HES. Dexpramipexole had been observed to produce a significant, targeted reduction of peripheral blood eosinophils in earlier clinical trials in amyotrophic lateral sclerosis.
Subjects with HES on glucocorticoid therapy were eligible for the study if they required ≥10 mg prednisone or equivalent for control of symptoms and eosinophilia. Prior to study treatment, subjects underwent a standardized glucocorticoid taper to determine their minimally effective glucocorticoid dose (MED). Subjects for whom the MED had been determined within the past year or with an eosinophil count ≥1000/µL at the time of enrollment were eligible to proceed directly to dexpramipexole treatment at the discretion of the principal investigator. After 12 weeks of oral dexpramipexole treatment (150 mg twice daily) on a stable glucocorticoid dose, a glucocorticoid taper was attempted and the MED on dexpramipexole (MEDD) was determined.
The trial enrolled 10 subjects and met the co-primary endpoints of: 1) percentage of subjects experiencing a ≥50% reduction in MED and 2) reduction of glucocorticoid requirement among all subjects. Notably, three of the four responders meeting the primary endpoint exhibited complete hematological responses (eosinophil count of zero or near-zero) and were able to discontinue prednisone completely. These subjects have remained symptom-free, eosinophil-free, and steroid-free for 13-32 months while continuing dexpramipexole treatment, as reported in the article.
The investigators also reported that three of four responders who underwent biopsies had complete resolution of eosinophilia in affected skin or gastrointestinal tissue. Delayed and partial hematological responses were also noted in the trial.
Dexpramipexole was well tolerated, with no adverse events leading to drug interruption or discontinuation.
The article concluded, "Well-tolerated and with a dosing schedule convenient for routine outpatient treatment, dexpramipexole shows great promise as a novel oral therapy for HES."
Michael Bozik, M.D., President and CEO of Knopp Biosciences, said, "The Blood publication demonstrates that dexpramipexole merits Phase 3 development in HES, a rare hematological disease with significant morbidity and limited treatment options. We are grateful for our collaboration with Dr. Klion and her NIH colleagues, and we look forward to initiating the Phase 3 study later this year."
HES comprises a heterogeneous group of rare disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. The NIH trial enrolled subjects with the FIP1L1-PGDFRA-negative form of the disease, which accounts for 85-90% of all HES. Although glucocorticoid therapy is the first-line treatment for patients with FIP1L1-PGDFRA-negative HES, many patients develop serious side effects or resistance over time.
The Phase 2 study was conducted as part of an agreement between Knopp Biosciences and NIAID, demonstrating industry-government collaboration in the field of rare disease drug development.
Ref : http://knoppbio.com/news-events/show.php?40


Wednesday, June 6, 2018

Study identifies molecule that may be critical to repair of white matter

In continuation of my update on hyaluronic acid (HA)

Hyaluronan.svg

A new study identifies a molecule that may be critical to the repair of white matter, the fatty tissue wrapped around parts of brain cells that helps speed up communication. Damage to white matter is associated with several conditions, including multiple sclerosis and cerebral palsy, and can occur in the brains of preterm babies. New findings suggest that the molecule triggers a pathway that is normally used by the immune system to prevent excessive damage but may contribute to chronic white matter injury by completely blocking repair operations. The study, published in the May issue of Journal of Clinical Investigation, was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"This study uncovers a new player in white matter disease and identifies a potential drug target," said Jim Koenig, Ph.D., program director at NINDS. "It also describes a unique situation in which the brain tries to take over immune system functions, with devastating results."
White matter, also known as myelin, is formed by oligodendrocytes, specialized cells that come from developing cells called oligodendrocyte progenitor cells (OPCs). Studies have shown that in cases of chronic white matter injury, OPCs accumulate in the lesions, ready to help, but for some reason are not able to produce myelin. A very large molecule called hyaluronic acid (HA) also accumulates in the lesions and is broken down into small fragments that are thought to prevent OPCs from producing myelin.
A team led by Stephen Back, M.D., Ph.D., professor of pediatrics and neurology at the Oregon Health & Science University in Portland, took a detailed look at the HA fragments to see how they block myelin repair. Using state-of-the-art techniques, Dr. Back and his colleagues were able to create HA fragments of different sizes.
Results showed that only one specific size of HA, the 210 kDa fragment, had an effect on OPC proliferation.
Dr. Back and his team treated rat cells that mimicked white matter disease with the 210 kDa HA fragment. They discovered that the HA initially turned on molecules associated with myelination but then shut them down completely, a strategy that is similar to immune tolerance, which is used by the immune system to prevent severe tissue injury from an ongoing, damaging response to bacteria and viruses.

"We showed that HA creates not just a roadblock to myelin repair after injury, it also shuts down all of the possible detours," said Dr. Back. "Tolerance can be helpful in preventing the brain from repairing itself too quickly, but in some disease conditions, it can turn into a detrimental response."
Dr. Back and his team also discovered that the 210 kDa fragment signals to TLR4, a protein that oversees immune tolerance, to activate FoxO3, which helps control the activity of genes involved in myelin repair. This activation of FoxO3 eventually leads to a decrease in the activity of myelin-related genes and a slowdown in white matter repair. However, this process only takes place if HA is present.
When Dr. Back and his group looked at human brain tissue affected by white matter injury and multiple sclerosis, they found activated FoxO3 in OPCs that were blocked from producing myelin.
In the brain, the large, intact HA makes up most of the extracellular matrix, the substance found between cells. Damage to the extracellular matrix leads to inflammation and this can occur in white matter injury.
"For decades HA was thought of as simply a glue holding everything together. In recent years, we have come to learn how critical this molecule is for various pathways and potentially, many neurological disorders," said Dr. Back.
More research is needed to learn about the molecules involved in white matter repair as well as the role of different HA fragments in these processes.

Tuesday, June 5, 2018

Osteoporosis drug prevents spread of basal-like breast cancer in mice

In continuation of my update on zoledronic acid 
Zoledronic acid.svg
Researchers in China have discovered that an enzyme called UGT8 drives the progression of basal-like breast cancer, an aggressive form of the disease that is largely untreatable. But the study, which will be published May 4 in the Journal of Experimental Medicine, reveals that the widely used osteoporosis drug zoledronic acid inhibits UGT8 and prevents the spread of basal-like breast cancer in mice, suggesting that this drug could also be used to treat the disease in humans.
Basal-like breast cancer is a particularly aggressive form of breast cancer that typically affects younger, premenopausal women. It is hard to treat because the tumor cells are usually "triple negative," lacking the estrogen receptor, progesterone receptor, and HER2 protein that are the main therapeutic targets for other forms of breast cancer. As a result, the prognosis for patients with basal-like breast cancer is worse than any other breast cancer subtype.
"The highly aggressive nature and the absence of effective therapeutics for basal-like breast cancer make it a high priority to elucidate what determines its aggressiveness and identify potential therapeutic targets," says Professor Chenfang Dong from the Zhejiang University School of Medicine in Hangzhou, China.
Cancer cells must alter their metabolism in order to survive and metastasize to other parts of the body. Dong and colleagues examined over 5,000 breast cancer patient samples and found that levels of the metabolic enzyme UGT8 were dramatically elevated in patients with basal-like breast cancer. Higher UGT8 levels correlated with increased tumor size, higher tumor grade, and shorter patient survival times.
UGT8 catalyzes the first step in the synthesis of sulfatide, a type of lipid that is found on the surface of cells and has been implicated in cancer progression. Dong and colleagues found that breast cancer cells expressing high levels of UGT8 produce large amounts of sulfatide, which in turn activates signaling pathways crucial for the survival and metastasis of basal-like breast cancer. Depleting UGT8 from these cells lowered sulfatide levels and reduced the cells' ability to form tumors when injected into mice.
Zoledronic acid is a drug that is approved to treat a variety of bone diseases, including osteoporosis, and is on the World Health Organization's list of safe and effective medicines essential for global health. Dong and colleagues confirmed that zoledronic acid is a direct inhibitor of UGT8 that reduces the levels of sulfatide in basal-like breast cancer cells. Treatment with the drug impaired the cells' ability to invade their surroundings and, accordingly, prevented them from metastasizing to the lungs after they were injected into the mice.
"Our study suggests that UGT8 contributes to the aggressiveness of basal-like breast cancer and that pharmacological inhibition of UGT8 by zoledronic acid offers a promising opportunity for the clinical treatment of this challenging disease," Dong says.​
Ref :http://jem.rupress.org/content/early/2018/05/03/jem.20172048

Saturday, June 2, 2018

Baldness treatment using a medication for osteoporosis

According to study leader Nathan Hawkshaw, of the University of Manchester in England, this new drug has never been considered in the treatment of baldness. It has been seen that the this could promote human hair growth. He said this could make a difference to people suffering from hair loss one day. To become a reality however, the drug would need to pass through clinical trials that would show it is effective in re-growing hair and also safe for use.
The researchers explain that at present there are only two drugs – Minoxidil and Finasterite that can help temporarily and relatively unsuccessfully in male pattern of baldness. These drugs are however fraught with side effects and are not always successful. While minoxidil can be used for both men and women, finasteride is useful only in men.
Minoxidil A space filling model of the molecule.                            Finasterite Finasteride.svg
Hawkshaw and his colleagues thus went ahead to explore the drug WAY-316606 that was originally developed to stop bone loss seen in osteoporosis. The drug is shown to inhibit the production of a protein called SFRP1. This protein is responsible for hair loss and inhibits growths of several other tissues by blocking a WNT molecular pathway. When used on hair follicles thus, WAY-316606 showed benefits and hair regrowth.
                                                   img WAY-316606
The researchers used samples from the lab containing scalp hair follicles from over 40 male hair-transplant patients and were pleased to report encouraging results with the test drug.
Baldness or pathological hair loss
One of the most common forms of hair loss is male pattern baldness. It affects around 50% of men by time they reach the age of 50. It is usually hereditary and thought to be associated with having an excess of a certain hormones, which has an effect on hair follicles. The hair loss usually begins while a man is in his late 20s or early 30s. Female pattern baldness most commonly affects post-menopausal women, possibly as a result of hormonal changes. Alopecia areata commonly manifests as patchy baldness that may resolve and then recur. It can affect both men and women at any age. It is caused by an immune system disorder and people with autoimmune conditions are more likely to be affected. In one fifth of cases, alopecia areata is hereditary. Alopecia or baldness can also be due to scars or cicatricial alopecia. The hair follicles are completely destroyed and hair does not grow again. The condition affects both males and females and is more common among adults than children.
Ref : http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2003705

Friday, June 1, 2018

ONC201 disrupts mitochondrial function and kills breast cancer cells, reveals study

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TRAIL, a member of the TNF family of ligands, causes caspase-dependent apoptosis through activation of its receptors, death receptor 4 and DR5.
ONC201 was originally identified as a small molecule that inhibits both Akt and ERK, resulting in dephosphorylation of Foxo3a and thereby induces TRAIL transcription.
Recently, two independent groups, Wafik El Deiry at Fox Chase and Michael Andreeff at MD Anderson,reported that ONC201 induces cell death via cell stress mechanisms, independent of TRAIL transcription. Gene expression profiling analysis revealed that ONC201 induces endoplasmic reticulum (ER) stress or integrated stress response -related genes, such as Activating Transcription Factor 4 (ATF4) and C/EBP-homologous protein (CHOP).
The researchers in Dr. Lipkowitz's group at the Center for Cancer Research in the National Cancer Institute observed that ONC201 kills breast cancer cells via a TRAIL-independent mechanism. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. They found that ONC201 inhibits mitochondrial respiration and induces mitochondrial structural damage. Moreover, they found ONC201 reduces mitochondrial DNA copy number. Importantly, cells dependent on glycolysis, such as fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mitochondrial DNA were resistant to ONC201. ONC201 induced ATF4 and CHOP in breast cancer cells, and the stress response it was partially dependent on the mitochondrial effects of ONC201.
"Our work identifies a novel mechanism of ONC201 cytotoxicity that is based on the disruption of mitochondrial function, leading to ATP depletion and cell death in cancer cells that are dependent on mitochondrial respiration. Our study also suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201" Dr. Stanley Lipkowitz, Chief, Women's Malignancies Branch, NCI.
Ref : http://www.oncotarget.com/news/pr/onc201-kills-breast-cancer-cells-in-vitro-by-targeting-mitochondria