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An Old Drug with New Tricks: Hydroxychloroquine

The AHA! Team — Tue, 04 Feb 2025 06:24:47 +0000

Medical University of South Carolina via EurekAlert! – The anti-malarial drug hydroxychloroquine shows promise against cancer, but cancer cells often develop resistance. A new study from MUSC Hollings Cancer Center researchers discovered how, setting the stage for new combination therapies As the hunt for effective cancer therapies intensifies, some scientists are turning back to look at old drugs in a new light. The anti-malarial hydroxychloroquine is one such drug that has been “repurposed” to fight cancer. Despite its effectiveness at blocking the resupply of needed resources to cancer cells, clinical trial results have been disappointing, in part because cancer cells eventually become resistant to the drug. A Medical University of South Carolina Hollings Cancer Center team led by Joe Delaney, Ph.D., reports in Cell Cycle that resistance to hydroxychloroquine occurs not by restoring the cancer cells’ recycling ability, as had been expected. Rather, resistance develops due to changes in the division, metabolism and export pathways of cancer cells. These findings open the door for new combination treatments, as drugs targeting these newly identified resistance mechanisms can be administered along with hydroxychloroquine to improve outcomes. The promise of repurposed drugs Repurposing old drugs for new treatments is not a new concept. Aspirin was originally used as a painkiller, but after the discovery of its anti-coagulant properties, it was repurposed as a blood thinner to treat heart disease. Thalidomide, the infamous anti-nausea medication, has been recently repurposed as a treatment for certain types of cancer and even leprosy. As cancer therapy moves increasingly toward specific single-protein targets, some scientists, like Delaney, are swinging back to look at preexisting drugs to find robust, multi-target effects. “Targeting single proteins can be extremely effective to treat cancer,” said Delaney. “However, the more specific the treatment becomes, the more likely resistance is to occur.” Imagine a hotel hallway, and behind each door is a route for cancer development. Targeting single proteins is like welding one of the doors shut. It’s impossible to get through that door, but it’s just a matter of time before cancer picks the lock on another door and gets in. That’s why these old drugs are so promising, said Delaney – their breadth of targets padlocks several doors at once, making it that much harder for a cancer cell to work around them. “These older molecules usually work because they have many, many targets within the cell,” he said. “If we can figure out how to use them correctly, it’s harder for cancer cells to mutate all those different points that they are acting on.” The cancer-fighting promise and limitations of hydroxychloroquine Originally used as a treatment for malaria, hydroxychloroquine began to be explored as a cancer therapy in the mid-2000s. The drug is known to block autophagy, a process that essentially acts as a cell’s clean-up crew. Autophagy literally means “self-eating.” It enables cancer cells to gather up old or damaged cellular machinery and send it off either to be thrown out or recycled. “When we think of cancer, we think of uncontrolled dividing cells,” said Delaney. “Autophagy is one of those processes that really enables a cancer cell to do just that by resupplying it with resources needed for survival and division.” Despite the drug’s promise of killing cancer cells by blocking cellular recycling, most clinical trials using the drug have been disappointing. “What we don’t know is why so many of these clinical trials have failed,” said Delaney. “We’re trying to figure out why hydroxychloroquine works or doesn’t work in certain situations in cancer.” A surprising finding about resistance to hydroxychloroquine To answer these questions, researchers in the Delaney Lab embarked on a multi-omics exploration into hydroxychloroquine’s effect on ovarian and colorectal cancer cells. They treated cells with hydroxychloroquine and then used two different whole-genome screens to identify exactly what the cells were doing to evade hydroxychloroquine attacks. With these approaches, they were able to observe how cells activated or deactivated different cellular pathways in response to continued hydroxychloroquine exposure. “By using two completely different methods, we were able to home in on the true biological players in the system,” said Delaney. The researchers were surprised to find that cells weren’t modifying autophagy to survive –the door that was expected to be opened really wasn’t touched at all. Instead, cancer cells were surviving hydroxychloroquine by changing their metabolism, division and export pathways. “We thought the main interaction of hydroxychloroquine with cancer was this process of autophagy, but it appears instead that processes unrelated to autophagy may be the most important for cancer cells to survive this therapy,” said Delaney. Setting the stage for novel combination therapies With this discovery, the Hollings team hopes to identify drugs that could be administered along with hydroxychloroquine to prevent the cancer cells from becoming resistant to this therapy. “Our study has identified the potential mechanisms that we will need to target with a second drug to prevent resistance against hydroxychloroquine,” said Delaney. Combining hydroxychloroquine with drugs that affect cell division, metabolism or export could increase the effectiveness of the treatment. Additionally, using hydroxychloroquine to treat patients with cancers that already have defects in one of these newly identified pathways could be a very powerful intervention. Finally, patients without these defects could be directed to potentially more effective, less resistant treatments. “We certainly want to understand which patients would see the most benefit to get the best result from these trials,” Delaney said. Ultimately, these results from the Delaney Lab shed light on how repurposed drugs like hydroxychloroquine can be used to fight cancer more effectively. Specifically, they show that cancer cells resist hydroxychloroquine in unexpected ways. By using such information, scientists can create more effective combination treatments against cancer. # # # About MUSC Hollings Cancer Center MUSC Hollings Cancer Center is South Carolina’s only National Cancer Institute-designated cancer center with the largest academic-based cancer research program in the state. With more than 150 faculty cancer scientists and 20 academic departments, it has an annual research funding portfolio of more than $50 million and sponsors more than 200 clinical trials across the state. Hollings offers state-of-the-art cancer screenings, diagnostic capabilities, therapies and surgical techniques within its multidisciplinary clinics to provide the full range of cancer care. Dedicated to preventing and reducing the cancer burden statewide, the Hollings Office of Community Outreach and Engagement works with community organizations to bring cancer education and prevention information to affected populations. For more information, visit hollingscancercenter.musc.edu Journal Cell Cycle DOI 10.1080/15384101.2024.2402191 To read the original article click here.

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Hydrogels Offer New Hope for Cancer Treatment

AHA Publisher — Fri, 16 Apr 2021 07:00:10 +0000

Tokyo University of Science via News-Medical – Hydrogels are often used as drug delivery systems, but to be effective carriers for anti-cancer drugs, they need to be responsive to varied stimuli in the tumor microenvironment. Now, scientists from Japan have developed novel hydrogels to effectively deliver drugs to tumor sites in response to temperature and pH changes in the tumor microenvironment. These multi-stimuli-responsive hydrogels can eliminate remnant cancer cells following tumor excision through controlled drug release, offering hope for effective cancer treatment. Cancer therapy in recent times relies on the use of several drugs derived from biological sources including different bacteria and viruses, among others. However, these bio-based drugs get easily degraded and therefore inactivated on administration into the body. Thus, effective delivery to and release of these drugs at target tumor sites are of paramount importance from the perspective of cancer therapy. Recently, scientists have discovered unique three-dimensional, water-containing polymers, called hydrogels, as effective drug delivery systems (DDSs). Drugs loaded into these hydrogels remain relatively stable owing to the network-like structure and organic tissue-like consistency of these DDSs. Besides, drug release from hydrogels can be controlled by designing them to swell and shrink in response to certain stimuli, or minute changes in conditions, like temperature or pH (which determines the acidity of an environment). For instance, when conditions are just the right level of acidic in the tumor microenvironment, these DDSs either shrink or swell and release the drug. However, there has been no method for the one-pot synthesis of hydrogels that respond to more than one such stimulus and degrade to release drugs at target tumor sites. Until now. Now, a team of scientists, led by Professor Akihiko Kikuchi from Tokyo University of Science, reports the production of unique degradable hydrogels that respond to changes under multiple conditions in “reducing” environments mimicking the microenvironment of tumors. In order to prepare degradable hydrogels that can release drugs in response to changes in the tumor microenvironment, we prepared hydrogels that respond to temperature, pH, and reducing environment, and analyzed their properties.” (Akihiko Kikuchi, Professor, Tokyo University of Science) In their study published in the Journal of Controlled Release, Prof. Kikuchi–along with his colleagues from Tokyo University of Science, Dr. Syuuhei Komatsu, Ms. Moeno Tago, and Ms. Yu Ando, and his collaborator on the study, Prof. Taka-Aki Asoh from Osaka University–details the steps of designing these novel hydrogels from the synthetic polymer poly(ethylene glycol) diglycidyl ether and the sulfur-containing organic compound cystamine. In response to low temperatures, these hydrogels swell up while they shrink at the physiological temperature. Additionally, the hydrogels respond to pH changes by virtue of possessing tertiary amino groups. It must be noted here that the pH of the tumor microenvironment fluctuates between 5.5 and 6.5 owing to glycolysis in the tumor cells. Under the reducing conditions of this environment, the hydrogels degrade because of the breakage of disulfide bonds and change into low molecular-weight water-soluble oligomers that are easily excreted from the body. To further test their drug release properties, the scientists loaded these hydrogels with specific proteins by exploiting their temperature-dependent swelling-deswelling behavior and tested the controlled release of drugs under acidic or reducing conditions. It was found that the amount of drug loaded onto these hydrogels could be controlled by changing the mesh size of the hydrogel polymer network by changing temperature, suggesting the possibility of customizing these DDSs for specific drug delivery. Besides, the hydrogel network structure and electrostatic interactions in the network ensured that the proteins were preserved intact until delivery, unaffected by the swelling and shrinking of the hydrogels with pH changes in the surrounding environment. The scientists found that the loaded protein drugs were completely released only under reducing conditions. Using these hydrogels and the tractability that they provide, doctors may soon be able to design “customized” hydrogels that are specific to patients, giving personalized medicine a big boost. In addition to that, this new DDS provides a way to kill cancer cells that are left behind after surgery. “The implantation of this material in the affected area after cancer resection may eliminate residual cancer cells, making it a more powerful therapeutic tool”. (Akihiko Kikuchi) As cancer tightens its vise grip around the world, treatment options need to be varied and upgraded for customized and effective therapy. This unique and simple design technique to produce multi-stimuli-responsive hydrogels for effective drug delivery to target tumor sites may just be one among several such promising techniques to mount an answer to the challenge cancer poses to humanity. To read the original article click here.

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Researchers Identify New Drug Combination That Can Treat Acute Myeloid Leukemia

AHA Publisher — Fri, 22 Jan 2021 08:00:57 +0000

Sanford Burnham Prebys Medical Discovery Institute via News-Medical Net – Scientists have identified two drugs that are potent against acute myeloid leukemia (AML) when combined, but only weakly effective when used alone. The researchers were able to significantly enhance cancer cell death by jointly administering the drugs that are only partially effective when used as single-agent therapies. The study, a collaboration between Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow, was recently published in the journal Nature Communications. Our study shows that two types of drugs, MDM2 inhibitors and BET inhibitors, work synergistically to promote significant anti-leukemia activity. The results were surprising because previous research had shown that each drug on its own had modest benefit against AML. The new research provides scientific rationale to advance clinical studies of the drug combination in patients with AML.” (Peter Adams, Ph.D, Study Senior Author and Professor, Sanford Burnham Prebys Medical Discovery Institute) There are many types of AML, and different cases have different chromosome changes, gene mutations and epigenetic modifications, making it difficult for researchers to find novel therapies that will work for a substantial proportion of patients. Although much progress has been made toward finding effective treatments in recent years, the long-term overall survival has stagnated. According to the American Cancer Society, the five-year survival rate for adults with AML remains less than 30%. Notably, TP53, the most frequently mutated gene in all human cancers, is found unaltered in about 90% of AML patients. Since the product of the TP53 gene, p53, acts to suppress tumors, scientists have sought drugs that reactivate or boost its anti-cancer powers in AML, which should provide a clinical benefit. However, such drugs on their own have been disappointing in AML. “We were interested in combining MDM2 and BET inhibitors because each showed encouraging pre-clinical activity, but limited activity when given to patients as a single agent,” says Adams. “Previous research had shown that MDM2 inhibitors activate p53, and BET inhibitors suppress genes associated with leukemias–but not p53. “Our research unexpectedly showed that like MDM2 inhibitors, BET inhibitors activate p53, but through a different pathway. BET inhibitors mute the power of a protein called BRD4, which we found is a p53 suppressor in AML,” says Adams. “Between the two drugs, you end up with a ‘double whammy’ effect that fully unleashes the anti-cancer activity of p53. “Better therapies for AML are desperately needed,” adds Adams. “This study illustrates that targeting BRD4 as part of a combination therapy holds promise for patients diagnosed with this very dangerous disease.” To read the original article click here.

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Exploiting Careless Cancer Cells to Develop New Drugs

AHA Publisher — Wed, 18 Mar 2020 07:00:33 +0000

Uppsala University via News-Medical Net – Could the ability of cancer cells to quickly alter their genome be used as a weapon against malignant tumors? Researchers at Uppsala University have succeeded in developing a substance that has demonstrated promising results in experiments on both animal models and human cancer cells. The study is published in the journal Nature Communications. Could the ability of cancer cells to quickly alter their genome be used as a weapon against malignant tumors? Researchers at Uppsala University have succeeded in developing a substance that has demonstrated promising results in experiments on both animal models and human cancer cells. The study is published in the journal Nature Communications. It is typical of cancer cells that they can quickly alter their DNA; however, in their haste to acquire new mutations, they carelessly discard many of their inherited genetic variations. This may lead to cancer cells only retaining a defective allele of a gene from one parent, whereas healthy cells also have a functioning allele from the other parent. This characteristic of cancer cells may well be an Achilles heel that can be utilized in the development of new drugs. “We searched for genes of which many people carry both a functioning and defective allele in their DNA. One such gene, NAT2, produces a protein that metabolizes a number of drugs and is of particular interest as one allele is often lost during the development of colon and rectal cancer.” (Tobias Sjöblom of Uppsala University’s Department of Immunology, Genetics and Pathology) Based on their discovery, the researchers developed a substance that kills cells lacking NAT2 and were also able to demonstrate that it can be used to treat animal models of cancer and tumor cells from patients. “The conditions for treatment exist in 50,000 of the colorectal cancer patients diagnosed globally each year and we will therefore continue working to identify substances with even better properties for pharmaceutical development,” says Tobias Sjöblom. To read the original article click here.

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