By Dr. Chinta Sidharthan Reviewed by Danielle Ellis, B.Sc. Nov 21 2024
Researchers identify gliocidin, a blood-brain barrier-penetrating prodrug, that targets glioblastoma's unique metabolic vulnerability, offering a promising therapeutic strategy and extended survival in preclinical models. Study: Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma. Image Credit: April stock/Shutterstock.com
In a recent study published in Nature, a team led by researchers from Memorial Sloan Kettering Cancer Center investigated the effects of the compound gliocidin in targeting glioblastoma, an aggressive form of brain tumor.
The study found that gliadin acts on specific cellular pathways to selectively kill glioblastoma cells without harming normal cells. Moreover, the compound can penetrate the blood-brain barrier, which highlights its potential as a treatment option for glioblastoma. Background
Glioblastoma is one of the most lethal forms of brain cancer and is known for its resistance to standard therapies. Despite significant advances in cancer therapies, currently used immunotherapies and targeted therapies have had minimal success in improving survival rates in glioblastoma. This resistance is believed to stem from several challenges unique to glioblastoma, such as its complex cellular heterogeneity and immune-evasive characteristics.
Additionally, crossing the blood-brain barrier to reach tumor cells remains a significant obstacle. Researchers are exploring novel metabolic pathways as potential therapeutic targets. Unlike typical cancer drugs that inhibit cell division, some emerging therapies aim to disrupt cancer-specific vulnerabilities. The use of prodrugs, which are converted into active drugs within the body, is gaining special attention due to their ability to target malignant cells while sparing healthy tissue selectively. About the study
In the present study, the researchers aimed to identify a compound that could selectively target glioblastoma cells. A high-throughput chemical screen of over 200,000 compounds was conducted using low-passage glioblastoma cells derived from genetically engineered mouse models. Compounds toxic to normal replicative cells were excluded. The screening identified gliocidin as a promising candidate due to its selective toxicity against glioblastoma cells.
To investigate the mechanism of action, the team then employed multiple experimental approaches. Genetic analyses were performed using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) screens to identify pathways and enzymes essential for the activity of gliocidin.
Pharmacokinetics and biodistribution studies in animal models were used to determine the ability of gliocidin to cross the blood-brain barrier and maintain effective concentrations in the brain. The researchers used glioblastoma-bearing mouse models to test the brain penetration abilities and bioavailability of gliocidin. Drug administration was optimized using intraperitoneal injection, and tissue analysis was used to confirm its presence in the brain.
Additionally, the researchers used liquid chromatography-mass spectrometry (LC-MS) to measure the levels of intermediate compounds and final metabolites in cells and tissues to understand gliocidin metabolism. Related StoriesStudy defines three subtypes of Chiari type-1 malformation to guide treatmentSpecific redox protein identified as a critical regulator of ferroptosisCannabis use linked to brain changes in young adults at risk of psychosis
Structural studies, including cryo-electron microscopy, were also conducted to characterize the interaction between the active form of gliocidin, gliocidin-adenine dinucleotide (GAD), and the enzyme inosine monophosphate dehydrogenase 2 (IMPDH2), to understand the binding mechanisms involved in gliocidin activation and metabolism. Gliocidin was also tested in combination with temozolomide, a standard chemotherapeutic for glioblastoma, to evaluate potential synergistic effects. Results
The study found that gliocidin effectively targeted glioblastoma cells by exploiting specific metabolic vulnerabilities of the cancer cells. Gliocidin was metabolized into GAD within the NAD+ salvage pathway, which then indirectly inhibited IMPDH2, a key enzyme in the purine synthesis pathway. This inhibition was found to lead to a severe reduction in guanine nucleotide levels, causing replication stress and cell death in glioblastoma cells.
Furthermore, the biochemical assays confirmed that gliocidin selectively disrupted guanine nucleotide synthesis in glioblastoma cells without affecting normal cells. The study demonstrated this specificity across multiple glioblastoma cell lines and patient-derived xenograft models. Additionally, the pharmacokinetic studies revealed that gliocidin successfully crossed the blood-brain barrier and accumulated in the brain, ensuring sustained exposure of the cancer cells to the compound.
Moreover, the in vivo studies in glioblastoma-bearing mice also showed that gliocidin monotherapy significantly suppressed tumor progression. When combined with temozolomide, a standard glioblastoma treatment, gliocidin produced synergistic effects, leading to greater tumor reduction and improved survival outcomes. An analysis of tumor samples from treated mice revealed that the combination therapy enhanced glioblastoma cell death by targeting both proliferative and non-proliferative tumor cells.
The researchers also found that gliocidin’s efficacy depended on nicotinamide nucleotide adenylyltransferase 1 or NMNAT1, an enzyme in the NAD+ salvage pathway. Tumors with higher NMNAT1 expression showed greater sensitivity to gliocidin. Interestingly, combination therapy with temozolomide was found to increase NMNAT1 expression further, amplifying the anti-tumor effects of gliocidin. Conclusions
Overall, the results established that gliocidin could selectively kill glioblastoma cells by disrupting critical nucleotide synthesis pathways. Its ability to penetrate the brain highlights its potential as a promising treatment for glioblastoma.
Furthermore, the enhanced efficacy observed when gliocidin was administered in combination with temozolomide further supports the potential of gliocidin as a future therapeutic approach for glioblastoma patients. Journal reference: Chen, Y.J., Iyer, S. V., Hsieh, D.C.C., Li, B., Elias, H.K., Wang, T., Li, J.,… Parada, L.F. 2024. Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma. Nature. doi: 10.1038/s41586-024-08224-z https://www.nature.com/articles/s41586-024-08224-z
Billionaire Jeff Bezos is marrying Lauren Sanchez, a former TV journalist, in a glitzy multi-day event in Venice.
While city officials haven’t confirmed the wedding details, Italian media have reported it will be a three-day affair between Tuesday and Thursday.
They also say it will take over the whole island of San Giorgio opposite St Mark’s Square – but that the location of the ceremony itself remains private.
Oprah Winfrey, Mick Jagger and Ivanka Trump are expected to attend, as is pop star Katy Perry, who joined Ms Sanchez in the all-female celebrity crew that travelled to space in April.
They and other celebrity guests – rumoured to include Leonardo Dicaprio and Eva Longoria – are expected to be joining the couple for parties on Amazon owner Bezos’s super yacht, worth about $500m (£371m), which will dock in the port of Venice for the wedding, Sky News Italy reports.
But not everyone in the iconic city is excited.
What protests are planned?
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Members of the group No Space for Bezos are planning to disrupt celebrations and have already made clear that, to them, the billionaire is not welcome in the city.
They unfurled a massive banner on 12 June from the bell tower of the San Giorgio Maggiore basilica with Bezos’s name crossed out.
Image: An anti-Bezos sign hung on the bell tower of the San Giorgio Maggiore basilica. Pic: Federica Toninelli
They are planning another demonstration on 28 June where they will block guests from arriving at a party by blocking the canals with boats and their bodies.
They say the protest will be peaceful.
“We want to take back our city that we are seeing constantly being privatised and taken away from us,” Federica Toninelli, an activist associated with No Space for Bezos, told Sky News.
Why are there protests?
Protesters do not have an issue with the marriage itself but with what they say is the “privatisation” and “exploitation” of the city.
Image: Lauren Sanchez and Jeff Bezos at Donald Trump’s inauguration. Pic: Reuters
“He is basically going to treat the whole city as a private ballroom, as a private event area, as if the citizens are not there,” said Alice Bazzoli, also an activist with No Space for Bezos.
Both told Sky News that the event will close parts of the city and make it difficult for locals to get around, as well as posing environmental concerns with the use of yachts in the canals.
“This is not what Venice needs. This is not what a city that is already suffering from overtourism needs,” said Ms Toninelli.
Image: No Space For Bezos protesters gather in Venice. Pic: Federica Toninelli
The city has long struggled with high tourism numbers.
Millions come to see a World Heritage Site famous around the world for its medieval architecture, crammed into a picturesque canal network.
But this pushes up the cost of living for locals and tends to create only low-paid temporary employment.
“It’s going to bring money, yes, but weare not going to see any money,” said Ms Toninelli.
Image: St Mark’s Square filled with tourists. Pic: Reuters
The protests are also linked to wider issues around affordable housing and a dwindling local population in Venice’s historic centre.
“Do we want our city even more invaded by tourists, by oligarchs, and people who buy and privatise the city, or do we want services, jobs, health services, schools, universities? Do we want to live in the city like normal people, or sell it to the best offer?” said Ms Bazzoli.
What has the response been to the protests?
The mayor of Venice, Luigi Brugnaro, says he is “honoured” that the city is hosting the event.
“Once again Venice proves to be a world stage,” he said.
“Those 20 people who are putting up posters are clearly capitalising on [Jeff Bezos’s] image.”
The city of Venice has previously denied that the event would disrupt locals, saying water taxi services would run normally and that only 200 guests had been invited.
“Venice is used to being the stage for events and shows every week, without significant impacts,” the city said, citing G20 and G7 summits, the Architecture and Cinema Biennales, as well as private events.
They say the city has previous experience of hosting big events successfully.
Is this the first celebrity Venice wedding?
No, George and Amal Clooney famously got married there in 2014.
The actor arrived at his ceremony at the Aman Grande Canal Hotel on a boat, alongside guests including Matt Damon and model Cindy Crawford.
The city also hosted world leaders for the 2021 G20 summit, as well as the annual Venice Film Festival.
Is tourism a problem in Venice?
Image: Day-trippers take a gondola tour in July 2024. Pic: Reuters
Venice has been struggling with the impacts of overtourism – when the number of visitors to an area worsens the experience of being there for locals or other tourists.
There were around 50,000 people living in the historic city centre in 2023 when there were around 4.9 million tourist arrivals, according to the data gathering website Statista.
In 2024, it became the first city in the world to introduce a payment system for tourists, with officials carrying out random checks to make sure people beyond entry points have a QR code.
As it stands, those visiting between April and July for a day trip pay a standard fee of €5 – unless they have booked less than four days before their visit, in which case they must pay double.
The city has also put in place a size limit of 25 people for tourist groups to reduce crowds.
Where else have there been tourist protests?
Venice isn’t the only European city where locals are frustrated with tourist numbers.
Protesters in Barcelona sprayed tourists with water guns as part of demonstrations over the number of visitors.
It would be sensible to wait until the dust has settled before judging whether the US strikes on Iran were, in Donald Trump’s, words, “a spectacular military success”.
And when dropping bombs that weigh more than 13 tonnes each, there’s going to be a lot of dust.
The Pentagon says the operation against Iran’s three largest nuclear facilities involved 125 military aircraft, warships and submarines, including the largest operational strike by B2 bombers in history.
The B-2s dropped 14 of America’s most powerful GBU-57 “bunker buster” bombs on the Natanz uranium enrichment plant and Iran’s most sophisticated nuclear facility at Fordow.
The first time, according to the Pentagon, the weapons have been used in a military operation.
The Fordow complex, buried deep in a mountain, was the only site not previously damaged by Israeli strikes over the last few days.
Image: A bunker-busting bomb. File pic: US Air Force via AP
The use of multiple GBU-57 bombs at Fordow is telling.
Despite their size, it was known that one of them would be insufficient to penetrate 80+ metres of solid rock believed to shelter Iran’s most sophisticated uranium enrichment technology deep within Fordow.
Satellite images reveal three visible holes at two different strike points on the mountainside above the complex.
Image: A satellite image showing two clusters of holes at the Fordow nuclear site in Iran following US strikes on the facility. Pic: Maxar
The sites appear to be close to what may have been ventilation shafts – possibly chosen to maximise damage below and render the facility useless.
Using several of the bombs in the same location is likely designed to allow each to penetrate further than the first before detonating.
If nuclear facilities at Isfahan, Natanz and Fordow were destroyed – as the US claims – or even crippled, it would certainly halt Iran’s ability to enrich the Uranium needed to make a viable nuclear weapon.
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7:22
Clarke: The dust will need to settle before we know true impact of US strikes
But that’s not the same as preventing Iran’s ability to make a nuclear bomb. To do that, they need “weapons-grade” uranium; the necessary metal-shaping, explosives and timing technology needed to trigger nuclear fission in the bomb; and a mechanism for delivering it.
The facilities targeted in the US raid are dedicated to achieving the first objective. Taking naturally occurring uranium ore, which contains around 0.7% uranium 235 – the isotope needed for nuclear fission – and concentrating it.
The centrifuges you hear about are the tools needed to enrich U-235 to the 90% purity needed for a compact “implosion”-type warhead that can be delivered by a missile.
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0:36
Iranian media: ‘Part of Fordow’ attacked
And the reality is Iran’s centrifuges have been spinning for a long time.
United Nations nuclear inspectors warned in May that Iran had at least 408kg of uranium “enriched” to 60%.
Getting to that level represents 90% of the time and effort to get to 90% U-235. And those 400kg would yield enough of that weapons-grade uranium to make nine nuclear weapons, the inspectors concluded.
The second element is something Iran has also been working on for two decades.
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1:44
‘US strikes won’t end Iran’s nuclear programme’
Precisely shaping uranium metal and making shaped explosive charges to crush it in the right way to achieve “criticality”, the spark for the sub-atomic chain reaction that releases the terrifying energy in a nuclear explosion.
In its recent bombing campaign, Israel is thought to have targeted facilities where Iranian nuclear scientists were doing some of that work.
But unlike the industrial processes needed to enrich uranium, these later steps can be carried out in laboratory-sized facilities. Easier to pack up and move, and easier to hide from prying eyes.
Image: 16 cargo trucks line up at the entrance of the Fordow nuclear site on 19 June. Pic: Maxar Technologies
Given that it’s understood Iran already moved enriched uranium out of Fordow ahead of the US strike, it’s far from certain that Iran has, in fact, lost its ability to make a bomb.
And while the strikes may have delayed the logistics, it’s possible they’ve emboldened a threatened Iran to intensify its warhead-making capability if it does still have one.
Making a more compact implosion-based warhead is not easy. There is debate among experts about how advanced Iran is along that road.
But if it felt sufficiently motivated, it does have other, less sophisticated nuclear options.
Even 60% enriched uranium, of which – remember – it has a lot, can be coaxed to criticality in a much larger, cruder nuclear device.
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Details are emerging about the US strikes against Iran’s nuclear facilities.
The US military has provided details about which sites have been hit and what military elements have been used, as President Donald Trump hailed the attack on social media.
From the number of bunker buster bombs dropped to where they hit, here’s what we know so far.
The US’s most senior military official gave details of how the attack, named Operation Midnight Hammer, unfolded.
Image: A US Air Force B-2 Spirit bomber. File pic: Reuters
General Dan Caine, chairman of the US joint chiefs of staff, said that at midnight on Friday, a large “B-2 strike package of bombers” launched from the US, flying east across the Atlantic.
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To maintain the element of surprise, some other bombers flew west into the Pacific.
During the 18-hour flight, the planes underwent multiple rounds of refuelling.
As the seven B-2 bombers entered Iran, the US deployed “several decoys”, according to Gen Caine, and a US submarine launched more than two dozen Tomahawk cruise missiles at the Isfahan nuclear site.
At around 6.40pm EST on Saturday, the first B-2 bomber dropped two GBU 57 Massive Ordnance Penetrator weapons, known as bunker buster bombs, on Fordow.
“The remaining bombers then hit their targets,” said Gen Caine, with 14 GBU-57s dropped in total.
Bunker buster bombs are designed to explode twice. Once to breach the ground surface, and again, once the bomb has burrowed down to a certain depth.
Image: A satellite image showing two clusters of holes at the Fordow nuclear site in Iran following US strikes on the facility. Pic: Maxar
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This attack was the GBU-57s’ first operational use.
Image: A file picture of a GBU-57 bunker buster bomb, which was possibly used in the attack on Fordow. Pic: AP
More than 75 weapons were used in total, including 14 30,000lb GBU-57 bunker buster bombs, and 125 aircraft took part.
The New York Times reported a US official as saying a B-2 also dropped two of the GBU-57s on the Natanz nuclear site.
The B-2s were all heading back towards the US by 7.05pm (EST), Gen Caine added, and he said the US military were not aware of any shots fired at the American jets by Iranian aircraft or air defences on the ground.
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1:44
‘US strikes won’t end Iran’s nuclear programme’
Which sites were hit?
America says it has hit the three key locations in Iran’s nuclear programme.
Image: The US attacked the Fordow, Natanz and Isfahan nuclear sites in Iran
They include Isfahan, the location of a significant research base, as well as uranium enrichment facilities at Natanz and Fordow.
Natanz was believed to have been previously damaged in Israeli strikes after bombs disrupted power to the centrifuge hall, possibly destroying the machines indirectly.
Details about the damage in the US strikes are not yet known, although Mr Trump said the three sites had been “obliterated”.
The US secretary of defence Pete Hegseth said the US had “devastated the Iranian nuclear programme”.
However, most of the highly enriched uranium at the Fordow nuclear facility was moved to an undisclosed location ahead of the attack, a senior Iranian source told the Reuters news agency.
Personnel numbers were also reduced at the site, according to the report.
Image: 16 cargo trucks line up at the entrance of the Fordow nuclear site on 19 June. Pic: Maxar Technologies
Satellite images from Fordow show cargo trucks lining up at the entrance of the nuclear site in recent days.
How has Iran responded so far?
Iran’s foreign minister Abbas Araghchi warned that the US strikes “will have everlasting consequences”, adding that his country “reserves all options” to retaliate.
“The events this morning are outrageous and will have everlasting consequences,” Mr Araghchi wrote on X. “Each and every member of the UN must be alarmed over this extremely dangerous, lawless and criminal behaviour.”
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1:45
Sirens in Israel as Iran retaliates
Iran has requested an emergency meeting of the UN Security Council to “maintain international peace and condemn the US strikes”, according to state media.
Multiple places in Israel have been hit by Iranian missiles in response.
Several explosions have been heard over Tel Aviv with Israeli media saying missiles have hit northern and central Israel, including in Haifa, Ness Ziona, Rishon LeZion and Tel Aviv.
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0:30
Destruction in Israel after Iranian strikes
Sixteen casualties were reported by the country’s emergency services.
Abbas Golroo, head of the Iranian parliament’s foreign policy committee, also said in a statement on social media Iran could pull out of efforts to limit the spread of nuclear technology and weapons, called the Treaty on the Non-Proliferation of Nuclear Weapons (NPT).
He cited Article 10 of the treaty, which states that an NPT member has “the right to withdraw from the treaty if it decides that extraordinary events have jeopardised the supreme interests of its country”.