Monday, June 28, 2021

Drug commonly used as antidepressant helps fight cancer in mice

A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain's "happiness hormone."

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the  attack . Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

"MAOIs had not been linked to the immune system's response to cancer before," said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "What's especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn't as challenging as developing a completely new drug would be."

Recent advances in understanding how the  naturally seeks out and destroys , as well as how tumors try to evade that response, has led to new cancer immunotherapies—drugs that boost the immune system's activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared  from melanoma tumors in mice to immune  from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA's corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

"For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two," said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. "So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells."

Next, the researchers studied mice that didn't produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells—the immune cells that target cancer cells for destruction—produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as , which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system.

In the Science Immunology paper, the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer.

But the drugs also have a second role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

"It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells," Yang said.

Combining MAOIs with existing immunotherapies

Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That's because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules.

Studies in mice showed that any of three existing MAOIs—phenelzine, clorgyline or mocolobemide—either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven't tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers.

Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells' response to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.

"We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits," she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

Monday, June 14, 2021

Cancer drug shows potential against pseudo SARS-CoV-2 in lab tests

In continuation of my update on Lenalidomide

Despite the effectiveness of COVID-19 vaccines, treatments are still needed to combat this disease, which has killed millions of people and still kills thousands each day across the world. Scientists at the UNC School of Medicine conducted lab experiments showing how the cancer drug lenalidomide disrupts a cellular pathway in human cells so that pseudo-viruses derived from SARS-CoV-2—the virus that causes COVID-19—cannot enter cells to cause infection.

The research, published in a letter to the journal Signal Transduction and Targeted Therapy, shows the potential of an existing FDA-approved drug to help doctors treat the sickest COVID-19 patients.

The labs of Pengda Liu, Ph.D., and Guochun Jiang, Ph.D., both assistant professors in the UNC Department of Biochemistry and Biophysics, conducted this work. Liu is a member of the UNC Lineberger Comprehensive Cancer Center, and Jiang is a member of the UNC HIV Cure Center.

SARS-CoV-2, a novel coronavirus and the causative agent of COVID-19, has caused a global social and economic disruption, and there are still thousands of cases and death each day in the United States and around the world. Treatments to prevent severe illness and death are still needed.

In this research letter, the UNC team reported that a  called E3 ligase SPOP recognizes and protects the human cell surface receptor ACE2, which is the protein SARS-CoV-2 latches onto in order to gain entry into  to cause infection. Another protein called CK1 kinase triggers this recognition and protection of ACE2.

The researchers used the cancer drug lenalidomide to inhibit CK1 kinase activity in cell cultures and showed a substantial reduction in ACE2 protein levels in kidney cancer cells. Researchers used SARS-CoV-2 S protein conditioned pseudoviruses in vitro and found lenalidomide treatment reduced the effect of this infection on kidney-derived cells.

"We hope that our identification and tests for the efficacy of inactivating the SPOP/CKI signaling in reducing ACE2 protein expression to attenuate SARS-CoV-2 infection provides a timely investigation into new therapeutic directions to combat COVID-19," Liu said.

A next step could be to use animal models to see if the drug blocks real SARS-CoV-2.

Cancer drug shows potential against pseudo SARS-CoV-2 in lab tests

Friday, June 11, 2021

Melatonin shown to protect kidney damage caused by obesity with diabetes

In continuation of my update on Melatonin

Scientists from the University of Granada (UGR), the Hospital Universitario La Paz (Madrid), and the University of Texas (U.S.) have taken an important step in the fight against kidney damage and its progression toward kidney failure, which is closely related to diabesity (obesity with type 2 diabetes) and its complications.

Specifically, in two new studies recently published in the Journal of Clinical Medicine and Pharmaceuticals, researchers have developed an obese and diabetic rodent model and have shown that melatonin protects from kidney damage caused by diabesity.

The scientists have shown that chronic administration of melatonin at doses (10 mg/kg body weight/day) prevents mitochondrial and endoplasmic reticulum disruption, which play a critical role in the development and pathogenesis of kidney cell (nephron) damage, and its progression to renal failure.

Thus, it has been shown that melatonin prevents the impairment of the function and dynamics of cellular mitochondria, decreasing the increased production of oxygen free radicals (responsible for ). It also prevents pathological alteration in the function of the endoplasmic reticulum (another cell cytoplasmic organelle), which, in conditions of abnormally high oxidative stress, is related to an increase in programmed cell death (of the nephron) leading to the loss of renal functionality, as a preliminary step to the development of renal failure and the need for hemodialysis or transplantation.

The studies coordinated by the UGR show the efficacy of melatonin in halting the progression of renal damage mediated by mitochondrial damage and excess endoplasmic reticulum stress.

As the lead author of this study, Ahmad Agil, a researcher at the Department of Pharmacology of the UGR, says, "Kidney damage is caused by metabolic complications of obesity, such as diabetes, hypertension, blood lipid disorders or fatty liver disease. Given that the prevalence of these pathologies (collectively recognized as metabolic syndrome) continues to increase, kidney damage and its progression over time to  has become a health problem that affects millions of people worldwide, with a great socioeconomic cost, requiring hemodialysis facilities and/or kidney transplant services, with the corresponding compatibility studies required."

The importance of the work lies not only in the efficacy of melatonin in counteracting the two proposed mechanisms of renal damage (based on the alteration of mitochondrial function and dynamics and the function of the endoplasmic reticulum (ER)), but they also propose an alternative preventive treatment that would improve this renal function with a well-studied drug with a very high safety profile such as melatonin, which is a drug that in the EU must be prescribed by a doctor and is already administered in the treatment of insomnia.

The new findings have also been associated with an improvement in glomerular filtration rate and renal damage of the nephron, manifested in a decrease in creatinine clearance levels (the best marker of renal function), proteinuria, and in the improvement of renal structure, observed after histopathological study of the kidney.

These results are in line with those previously published by these researchers in the last 10 years, demonstrating that the pharmacological administration of melatonin constitutes another new strategy in the therapeutic approach to diabesity (central obesity and its type 2 diabetes) and its complications (such as hepatic steatosis, hypertension, lipid alteration, etc.).

"Our main challenge is the application of melatonin and other strategies such as intermittent fasting in the field of medicine, especially to address the possibility of a treatment perspective for the aforementioned pathologies (diabesity and its complications) that involve an increase in oxidative stress, and mitochondrial damage and associated meta-inflammation (inflammation of metabolic origin)," Agil says.

According to the results, melatonin could help treat kidney damage, which establishes the need to develop new clinical trials to test its effectiveness in humans. The next step is to investigate how it helps in the maintenance of mitochondrial and endoplasmic reticulum homeostasis, and to a greater extent, if melatonin therapy would allow delaying or stopping progressive renal damage by promoting its chronic pharmacological use in kidney repair and regeneration.

Melatonin shown to protect kidney damage caused by obesity with diabetes