Tag: chemotherapy

Categories : CancerTags :

Oxidative Stress Contributes to Multi-drug Resistance in Chemotherapy

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Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash

Researchers have found that oxidative stress plays a role the inevitable occurrence of multi-drug resistance during tumour therapy, which they report in the Journal of Biochemical and Molecular Toxicology. 

While chemotherapy is a mainstay of cancer treatment, it is often hindered by the development of drug resistance, eventually evolving into multidrug-resistance which renders most drugs ineffective. 

Multidrug resistance is responsible for over 90% of deaths in cancer patients receiving traditional chemotherapeutics or novel targeted drugs. Its mechanisms include elevated metabolism of xenobiotics, enhanced efflux of drugs, growth factors, increased DNA repair capacity, and genetic factors (gene mutations, amplifications, and epigenetic alterations).

The most well-known mechanism is the induction of Adenosinetriphosphate (ATP)-binding cassette (ABC) transporters by chemotherapeutic drugs. These transporters are highly expressed in cancer cells and pumped out chemotherapeutics to make the treatment ineffective. 

Earlier research had shown that non-substrate nanoparticles could induce multidrug resistance by inducing oxidative damage, suggesting that multidrug resistance could be induced by oxidative damage as well as the substrate. 

To confirm the this, Yin Jian and his team investigated the interaction of three chemical agents (ethanol, hydrogen peroxide, and doxorubicin) with ABC transporters using a lung cancer cell line (A549) as a model. 

Among the three chemicals, doxorubicin is the substrate of ABC transporter and chemotherapeutic drugs, while ethanol and hydrogen peroxide are small-molecule compounds, which have no relationship with the function of ABC transporter. 

“When the three substances enter the cells, they can cause significant oxidative stress inside cells,” said Yin.  

The elevated oxidative stress induced the expression of transporters, and the elevated transporters reduce intracellular oxidative stress by effluxing oxidized glutathione. In this process, pregnane X receptor played an important regulatory role. 

Their results suggested that non-substrate chemicals could also induce ABC transporter expressions similar to chemotherapeutic agents after inducing oxidative damage. This phenomenon could be regarded as a non-specific feedback of tumor cells/ABC transporters to external stimuli. 

The conclusions validated the relationship between multidrug resistance mechanisms and oxidative stress. This would help to design advanced strategies on how to enhance this mechanism to more effectively combat ABC transporter-mediated multidrug resistance.  

“Considering that peroxidative damage is the main source of the toxicity of current environmental pollutants, long-term exposure to environmental pollutants could not only induce direct toxicity, but also further threaten human health by inducing multi-drug resistance,” said Yin Huancai, another researcher from the team. 

Source: China Academy of Sciences

Categories : Cancer GeneticsTags :

How Cancer Cells Repair their DNA so Quickly

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DNA repair
Source: Pixabay/CC0

Research into how the body’s DNA repair process works has made a discovery into how the process works, and by understanding how cancer cells repair their DNA so rapidly may lead to potent new chemotherapy treatments.

One of the great mysteries of medical science is the ability of DNA to be repaired after damage, but complicating the study of this is how different pathways are involved in the repair process over the cell’s life cycle. In one of the repair pathways known as base excision repair (BER), the damaged material is removed, and proteins and enzymes work together to create DNA to fill in and then seal the gaps.

In a study appearing in Proceedings of the National Academy of Sciences, Eminent Professor Zucai Suo led a team that discovered that BER has a built-in mechanism to increase its effectiveness: it just needs to be captured at a very precise point in the cell life cycle.

In BER, an enzyme called polymerase beta (PolyB) fulfils two functions: It creates DNA, and it initiates a reaction to clean up the leftover ‘chemical junk’. Through five years of study, Prof Suo’s team learned that by capturing PolyB when it is naturally cross-linked with DNA, the enzyme will produce new genetic material 17 times faster than when the two are not cross-linked. This suggests that the two functions of PolyB are interlocked, not independent, during BER.

The research improves the understanding of cellular genomic stability, drug efficacy and resistance associated with chemotherapy.

“Cancer cells replicate at high speed, and their DNA endures a lot of damage,” Prof Suo said. “When a doctor uses certain drugs to attack cancer cells’ DNA, the cancer cells must cope with additional DNA damage. If the cancer cells cannot rapidly fix DNA damage, they will die. Otherwise, the cancer cells survive, and drug resistance appears.”

This research examined naturally cross-linked PolyB and DNA, unlike previous research that mimicked the process. Studies had previously identified the enzymes involved in BER but did not fully grasp how they work together.

“When we have nicks in DNA, bad things can happen, like the double strand breaking in DNA,” said Thomas Spratt, a professor of biochemistry and molecular biology at Penn State University College of Medicine who was not a part of the research team. “What Zucai found provides us with something we didn’t understand before, and he used many different methods to reach his findings.”

Source: Florida State University

Categories : Cancer COVIDTags :

COVID Vaccines less Effective in Patients Undergoing Chemotherapy

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Photo by National Cancer Institute on Unsplash

New research has found that patients undergoing active chemotherapy had a lower immune response to two doses of the COVID vaccine, although a third dose increased response.

“We wanted to make sure we understand the level of protection the COVID vaccines are offering our cancer patients, especially as restrictions were being eased and more contagious variants were starting to spread,” said Rachna Shroff, MD, MS, University of Arizona Health Sciences.

To find out, Dr Shroff and colleagues looked at 53 Cancer Center patients on immunosuppressive active cancer therapy, such as chemotherapy. They compared the immune response following the first and second dose of the Pfizer-BioNTech COVID vaccine with that of 50 healthy adults. 

After two vaccine doses, most of the cancer patients showed some immune response to the vaccine in that they had produced antibodies for SARS-CoV-2.

“We were pleasantly surprised,” said Deepta Bhattacharya, PhD, professor of immunobiology in the College of Medicine – Tucson. “We looked at antibodies, B cells and T cells, which make up the body’s defense system, and found the vaccine is likely to be at least partially protective for most people on chemotherapy.”

However, this  immune response was much lower than in healthy adults, and a few of the patients had no response to the COVID  vaccine. This translates to less protection against SARS-CoV-2, especially the now-dominant Delta variant.

Twenty patients returned for a third shot, which boosted the immune response for most. The overall group immune response after the third shot reached levels similar to those of people who were not on chemotherapy after two doses.

The results were published in Nature Medicine.

Source: University of Arizona Health Sciences

Categories : CancerTags :

How Cancer Cells Develop Resistance to Chemotherapy

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Source: National Cancer Institute on Unsplash

Researchers have found some answers as to why cancer cells can develop resistance to the cytotoxic drugs used in chemotherapy.

“We haven’t understood very much about how this resistance to chemotherapy develops and even less about how the microenvironment in cancer can affect the process,” said Kaisa Lehti, a professor at the Norwegian University of Science and Technology’s (NTNU) Department of Biomedical Laboratory Science.

Lehti has led this study into how cancerous tissues develop resistance to a particular form of chemotherapy, the results of which appear in Nature Communications.

If ovarian cancer is picked up early, almost all patients survive the first five years, while chances of survival are much worse if detected later. Finding effective treatment is therefore very important.

Platinum chemotherapy is one of the standard treatments for ovarian cancer, but cancer cells often develop resistance to this particular treatment. The reason lies in how the platinum-based cytotoxin itself can change the cancer cells and their environment.

Cytotoxin influences cancer cells and their environment
Lehti summed up the process: “The cytotoxin can change the way the cancer cells send and perceive signals and can modify the microenvironment around the cells.”

This change allows the cancer cells to withstand the damage caused by the cytotoxin—and can thus survive the chemotherapeutic attack. The researchers have found this key to the puzzle in a layer of tissue that often surrounds cancer cells.

“A fibrotic network of proteins, known as the extracellular matrix or ECM, surrounds the cancer cells, particularly the most aggressive ones,” said Lehti.

The fibrotic tissue, with the ECM network around the cancer cells, is mainly produced by normal connective tissue cells. But the cancer cells and connective tissue cells in the network can alter this tissue themselves.

“Previously, we haven’t known how the communication between the cancer cells and the extracellular matrix is affected by, or even itself influences, the development of cancer and its response to chemotherapy,” said Prof Lehti.

But it is now known that chemical and mechanical signals in the surrounding ECM tissue help cancer develop its ability to spread and to resist treatment.

“Certain signals from the ECM can critically change the cancer cells’ resistance to platinum-based cytotoxic drugs,” Prof Lehti explained.

In this way, the cytotoxin itself helps change both the microenvironment around the cancer cells and the ability of the cancer cells to sense their environment, and so resist the cytotoxin. By understanding this process, better therapies can be developed.

Source: MedicalXpress