Breaking News
April 23, 2019 - Sensory Sensitivity Tied to Constipation in Young Children
April 23, 2019 - More than half of internal medicine graduates choosing primary care
April 22, 2019 - Researchers discover good news for fish populations living on bleached coral reefs
April 22, 2019 - Plant-based diets associated with lower risk of heart failure
April 22, 2019 - Food Allergies Can Strike at Any Age
April 22, 2019 - Cerebro-facio-thoracic dysplasia – Genetics Home Reference
April 22, 2019 - Poverty leaves a mark on our genes
April 22, 2019 - Countdown to Big Data in Precision Health: When industry and academia converge
April 22, 2019 - The U.S government may account for up to $37.8 billion due to opioid epidemic
April 22, 2019 - Improving ACA’s Insurance Coverage Provisions will lead to better care for patients
April 22, 2019 - Study identifies possible therapeutic effects of curcumin on stomach cancer
April 22, 2019 - Hyaline fibromatosis syndrome – Genetics Home Reference
April 22, 2019 - Scientists use CRISPR for possible ‘bubble boy’ therapy
April 22, 2019 - Hematologist (and a mom, singer, actress and much more) stands up for diversity
April 22, 2019 - Novel AI voice tool can help diagnose PTSD
April 22, 2019 - Overlooked part of cell’s internal machinery may hold key to treating acute myeloid leukemia
April 22, 2019 - Soft bedding responsible for majority of sleep-related infant deaths, study reveals
April 22, 2019 - Study finds worse health-related quality of life among transgender adults
April 22, 2019 - MIT scientists reverse some behavioral symptoms of rare neurodevelopmental disorder
April 22, 2019 - Scientists find new therapy target for drug-induced liver failure
April 22, 2019 - Opioid dose variability could lead to increased risk of overdose, study suggests
April 22, 2019 - Newly developed model predicts salmonella outbreaks several months in advance
April 22, 2019 - Deep-learning model better predicts survival outcomes for lung cancer
April 22, 2019 - One in Three U.S. Adults Aged 35 to 44 May Have Drinking Problem
April 22, 2019 - Why the measles virus is so contagious
April 22, 2019 - Magnet ‘Zap’ to the Brain Might Jumpstart Aging Memory
April 22, 2019 - Immune response to gut microbes may be early indicator of type 1 diabetes
April 22, 2019 - Destination Limbo: Health Suffers Among Asylum Seekers In Crowded Border Shelter
April 22, 2019 - Research shows how dopamine contributes to sex differences in worms
April 22, 2019 - Marijuana users weigh less compared to non-users
April 22, 2019 - Research uncovers critical RNA processing aberrations in ALS and FTD
April 22, 2019 - Many cancer patients use marijuana and prescription opioids, study reveals
April 22, 2019 - Frailty may up fracture risk in patients with type 2 diabetes
April 22, 2019 - Study provides new insight into how obesity, insulin resistance can affect cognition
April 22, 2019 - Study seeks to better understand the genetic causes for hypospadias
April 22, 2019 - FDA grants approval of first generic naloxone nasal spray to treat opioid overdose
April 22, 2019 - FDA authorizes marketing of first medical device to treat ADHD
April 22, 2019 - Vanderbilt researchers to develop and test ‘safe harbor’ standards of care
April 22, 2019 - You’re probably brushing your teeth wrong – here are four tips for better dental health
April 22, 2019 - Pharmacy closures contribute to medication non-adherence among heart patients
April 22, 2019 - Using Edge AI technology to observe behavior of cattle
April 22, 2019 - Bacteria play a role in the development of stomach ulcers in pigs
April 22, 2019 - Hand Hygiene Compliance Poor in Task Transitions
April 22, 2019 - smoking could harm your baby
April 22, 2019 - Scientists identify rare, paradoxical response to antiretroviral therapy
April 21, 2019 - More TV, Tablets, More Attention Issues at Age 5
April 21, 2019 - Drug reduces risk of kidney failure in people with diabetes, study finds
April 21, 2019 - New research identifies novel link between antibiotic resistance and climate change
April 21, 2019 - Simple intervention can provide lasting protection for teens against junk food marketing
April 21, 2019 - The protein p38-gamma identified as a new therapeutic target in liver cancer
April 21, 2019 - Novel system enables researchers to study bacteria within mini-tissues in a dish
April 21, 2019 - Discovery of oral cancer biomarkers could save thousands of lives
April 21, 2019 - Geneva Exhibition committee gives gold medals to two medications developed by Kazan
April 21, 2019 - Scientists aim to minimize or eliminate hair loss during cancer treatment
April 21, 2019 - WiFi interacts with signaling pathways in the human brain
April 21, 2019 - Stroke Hospitalizations Down in Black, White Medicare Enrollees
April 21, 2019 - First common risk genes discovered for autism
April 21, 2019 - Researchers map auditory sensory system of the mouse brain
April 21, 2019 - Scientists Bring Pig’s Brain, Dead 4 Hours, Back to ‘Cellular Activity’
April 21, 2019 - Virtual reality a promising tool for reducing fears and phobia in autism
April 21, 2019 - New analysis lists out opportunities for U.S. medical schools to advance population health
April 21, 2019 - More sleep may help teens with ADHD focus and organize
April 21, 2019 - Breakthrough antibody treatment suppresses HIV without antivirals
April 21, 2019 - AveXis Data Reinforce Effectiveness of Zolgensma in Treating Spinal Muscular Atrophy (SMA) Type 1
April 21, 2019 - Is your hand pain arthritis, carpal tunnel or something else?
April 21, 2019 - Measles outbreaks may become more frequent if vaccination rates continue to decline
April 21, 2019 - Researchers succeed in accelerating process of creating 3D images
April 21, 2019 - Tiny worm mimics key genetic risk for Alzheimer’s
April 21, 2019 - Angry dreams explained by brain waves
April 20, 2019 - Parenteral Antimicrobial Tx at Home Burdens Children’s Caregivers
April 20, 2019 - Diabetes treatment may keep dementia, Alzheimer’s at bay
April 20, 2019 - New bandage-like biosensor collects and analyzes sweat
April 20, 2019 - A comprehensive, centralized database of bovine milk compounds
April 20, 2019 - Two new epigenetic regulators maintain self-renewal of embryonic stem cells
April 20, 2019 - New Evidence That Veggies Beat Steak for Heart Health
April 20, 2019 - Study reveals genes associated with heavy drinking and alcoholism
April 20, 2019 - Texas A&M AgriLife becomes the newest member of NutriRECS international consortium
April 20, 2019 - In most states, insurance won’t cover addiction treatments
April 20, 2019 - Computer-based memory games may be beneficial for individuals with fragile X syndrome
April 20, 2019 - Timing of food intake influences molecular clock in the liver of mice
Tapeworm drug targets common vulnerability in tumor cells

Tapeworm drug targets common vulnerability in tumor cells

image_pdfDownload PDFimage_print
gene
Credit: CC0 Public Domain

A drug used to treat tapeworm infections could also be used to fight a wide range of cancers, an A*STAR study suggests.

More than half of human cancers carry a mutation in the tumor suppressor gene p53, making it an attractive target for cancer therapy. Many research efforts have focused on directly or indirectly restoring p53 function in mutated cells, but the team, led by Chit Fang Cheok of A*STAR’s Institute of Molecular and Cell Biology, took a different approach. Instead of trying to fix p53, which mutates in hundreds of ways in cancers, they exploited the differences between wild-type and p53-deficient cells to develop a treatment based on the vulnerabilities of p53-deficient cancer cells, “targeting the loss of function, the absence of p53,” Cheok says.

The team tested the effect of 1,600 FDA-approved compounds on cultured colon cancer cells with normal and mutated versions of p53. The compound that was best at killing p53-deficient cells, rather than cells with p53, was niclosamide, a drug used to treat tapeworm infections. Subsequent tests showed that niclosamide was also effective against other p53-deficient cancer cell lines.

Niclosamide is known to affect cells by interfering with energy production in mitochondria (an effect known as ‘mitochondrial uncoupling’) and causing changes in fatty acid metabolism. Experiments showed that mitochondrial uncoupling is integral to niclosamide’s ability to selectively kill p53-deficient cells, but isn’t enough to explain it, since a similar amount of uncoupling was also seen in p53-positive cells. In other words, it was still unclear why the drug was more effective against p53-deficient cells. “We went on a long ‘Sherlock Holmes’-like journey to understand what was happening,” says Cheok.

They examined the metabolic profile of niclosamide-treated cells and found that the p53-deficient cells had significantly more of a fatty acid known as arachidonic acid. Their investigation revealed that the mitochondrial uncoupling caused by niclosamide increases the calcium concentration in a cell, which boosts the production of arachidonic acid.

The team showed that this increase is normally counteracted by p53, which switches on two genes that break down arachidonic acid, ALOX5 and ALOX12B. These genes were not activated in p53-deficient cells, allowing arachidonic acid to accumulate, and causing mitochondria to release a molecule known as cytochrome c, leading to programmed cell death. Future work may identify other drugs that activate the same pathway and could also be used to treat p53-deficient cancers. “We were able to join all these dots in a very surprising manner, which was very exciting,” says Cheok.

To confirm their model, the researchers knocked out ALOX5 and ALOX12B in cells with a working copy of p53. They found that the engineered cells were more sensitive to niclosamide treatment even though they had a functioning p53 gene. Likewise, knocking out ALOX5 and ALOX12B in p53-deficient cells did not increase their niclosamide sensitivity.

Finally, the team confirmed that niclosamide is effective against p53-deficient cancers in animals, and not only in cultured cells. They injected mice with cells from the colon cancer cultures and measured tumor progress following niclosamide treatment. Niclosamide reduced tumor growth by 50 per cent in mice which had received p53-deficient cells but had no effect on tumors in mice injected with p53-positive cells.

Based on their findings, the researchers have filed a patent for the use of niclosamide to treat p53-deficient cancers. Since this approach targets deficiency rather than a specific mutation, Cheok expects it to be effective against a broad spectrum of cancers. Niclosamide has been used to treat humans for decades and is listed by the WHO as an effective, safe, and cheap medicine, raising hope for its use a potent, safe therapy against a broad spectrum of cancers with non-functional p53.


Tapeworm drug could lead the fight against Parkinson’s disease


More information:
R. Kumar et al. Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers, Nature Communications (2018). DOI: 10.1038/s41467-018-05805-1


Provided by
Agency for Science, Technology and Research (A*STAR), Singapore

Citation:
Tapeworm drug targets common vulnerability in tumor cells (2019, March 18)
retrieved 21 March 2019
from https://medicalxpress.com/news/2019-03-tapeworm-drug-common-vulnerability-tumor.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.

Tagged with:

About author

Related Articles