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Therapeutic resistance/drug resistance is a very difficult problem in the clinical treatment of tumors
.
The occurrence of drug resistance mechanisms usually involves a variety of signaling pathways related to tumor survival, such as cell metabolism, proliferation, and redox state, which greatly limits the means including chemotherapy and targeted therapy
.
Some originally sensitive tumors may also develop drug resistance due to new mutations after targeted therapy for a period of time
.
Therefore, people are trying to find the common "weakness" of different cancer targets and develop a single treatment method for this "weakness", so as to overcome the resistance of tumor treatment
.
In recent years, cellular reactive oxygen species (ROS) have been found to be abnormally elevated in tumor cells, and are closely related to glycolysis, redox, and proliferation signal transduction, indicating that it may be this shared "weakness
.
"
Previously, researchers have been able to use a gas discharge technology-low temperature atmospheric plasma (CAP) to generate exogenous ROS
.
CAP has been approved by the FDA as a catheter-guided scalpel for routine tumor and neurosurgery operations, and has shown efficacy in clinical trials for head and neck cancer
.
In 2021, a research team from Xi’an Jiaotong University, Old Dominion University, and the University of Utah found that in a drug-resistant mouse model of chronic myelogenous leukemia (CML), the CAP treatment program developed by it can effectively block oxidation, including oxidation.
Three cancer survival-related pathways, including imbalance of reduction, glycolysis and cell proliferation, are restored, so the program is named Trident CAP (Tri-CAP)
.
Tri-CAP can also cause high-efficiency apoptosis of CML and primitive CD34+ hematopoietic stem and progenitor cells, but at the same time it has little effect on non-malignant control cells.
Its good performance in animal experiments also brings about overcoming the problem of drug resistance in leukemia The dawn
.
The research results will be published in the latest PNAS on December 21, 2021
.
Research results (Source: PNAS Magazine) The main problem with existing ROS therapy is that the effective concentration of ROS cannot be determined: too low a ROS level cannot induce apoptosis, and too high a level will activate the cancer-promoting HIF-α pathway
.
The team has overcome this problem well.
They used a plasma jet (speed 1.
9 L/min) to generate ROS in argon with an oxygen content of 3%, and the distance between the electrode and the cell culture medium was 30 mm
.
This CAP protocol can generate extremely low levels of ROS in cell-free media, which are far lower than the ROS levels required to activate the HIF-α pathway.
At the same time, the temperature, pH and other indicators of the media are almost unaffected
.
In normal cells, imatinib-resistant CML cells (BCR-ABLT315I cells) and imatinib-sensitive CML cells (BCR-ABLp210 cells), Tri-CAP can cause drug-resistant cells to produce abnormally low levels The transients of extracellular and intracellular ROS increased sharply, achieving selective lethality to drug-resistant cell lines
.
Tri-CAP treatment of cell-free medium (Source: PNAS Magazine) After Tri-CAP treatment, drug-resistant CML cells had higher levels of ROS (Source: PNAS Magazine).
Researchers further discovered that Tri-CAP stimulated low levels of ROS Break the redox balance in the cell
.
In the BCR-ABL1+ cell line, Tri-CAP disrupts the redox balance in two ways: excessive intracellular ROS production and weakened antioxidant defense
.
On the contrary, normal cells in the control group can quickly restore the redox balance after three times of the same treatment
.
After Tri-CAP treatment, the redox imbalance between drug-resistant and sensitive CML cells (source: PNAS) also found that Tri-CAP can also inhibit multiple key targets in tumor metabolism and reduce lactic acid production
.
It was found in drug-resistant BCR-ABLT315I cells that the protein expression levels of many key molecules in aerobic glycolysis, such as PKM2, HK1, HK2 and PDK1, gradually decreased within 0-48 hours after Tri-CAP treatment, HK1 Almost completely missing
.
After Tri-CAP treatment, drug-resistant CML glycolysis is inhibited (Source: PNAS Magazine) Lactic acid, a product of aerobic glycolysis, is one of the activators of the main tumor proliferation pathway PI3K/AKT/mTOR.
The team further tested this The effect of a therapy on the pathway, it was found that the molecular markers activated by the pathway, such as phosphorylated mTOR and phosphorylated AKT, were significantly reduced in drug-resistant CML cell lines, while in sensitive CML cell lines and control cells The increase in expression of HIF-α in tumors promotes a similar pattern in the expression level of tumor resistance
.
After Tri-CAP treatment, the drug-resistant CMLAKT/mTOR/HIF-1α pathway is activated (Source: PNAS Magazine).
In short, these results indicate that Tri-CAP can preferentially block redox homeostasis, glycolysis, and glycolysis in resistant CML.
Proliferation (AKT/mTOR/HIF-1α), the three key ways of cancer survival, revealed for the first time a tumor treatment method that has not been reported before
.
In addition, Tri-CAP can also induce apoptosis of drug-resistant cells
.
CD34+ hematopoietic cells and progenitor cells of CML patients treated with Tri-CAP showed a high rate of apoptosis
.
In vivo experiments have also proved that these therapies can reduce tumor formation and improve the survival rate of tumor-bearing mice
.
Tri-CAP-treated tumor-bearing mice have reduced tumor growth and prolonged survival (Source: PNAS Magazine) Traditional ROS generation treatments, including radiotherapy, usually rely on high levels of ROS to induce direct cancer cell death, but at the same time the tumor The activation of survival-related pathways makes the therapeutic effect limited
.
In contrast, this research cleverly solves this problem and provides a basis for future clinical research
.
In general, Tri-CAP is expected to be a potential therapy to overcome and prevent the drug resistance of a variety of malignant tumors
.
End's selection of onlookers in the past, the more you exercise, the smarter you are! Nature: "Athlete's blood" can resurrect sedentary mice with blood! Sub-Journal of Rewen Nature: The age of human death may be calculated, the greater the pressure, the faster the aging process.
Nature sub-published two articles in a row: Cancer cells "dormant" for several years, or the key factors that lead to cancer metastasis/recurrence.
Hot article "Nature" publishes "Top Ten People of 2021"! The chief designer of China's "Tianwen No.
1" and the tracker of the new crown virus variants are all on the list.
Be alert! Cell Reports: Potential star anti-cancer targets may promote cancer? Does this target have a future? Medical immunotherapy| Biosimilars| Vaccines| Drug resistance| Drug targets| Healthy life| Pharmaceutical company news| Drug inventory| Pharmaceutical technology| Basic research on side effects of drugs/ Translational medicine leukemia| Lung cancer| Gastric cancer| Colorectal cancer| Liver cancer| Breast Cancer | Pancreatic Cancer | Cardiovascular Diseases | Neurodegenerative Diseases | Intestinal Microbial Medical Devices / Biotechnology In Vitro Diagnosis | Medical Devices | Bio-Nano | 3D Printing | Gene Testing | Single Cell Sequencing | Gene Editing | Assisted Reproduction | Artificial Intelligence | Precision medicine policy anti-cancer drugs | 4+7 volume procurement | Consumables | Filing system | Registrant system | Healthy China | New edition of basic medicine catalog | AI medical equipment | Telemedicine | Same-share market with different rights/capital IPO | Financing | Cooperation | Funds | Hong Kong Stock Exchange | Science and Technology Innovation Board | Growth Enterprise Market | R & D Investment | Acquisitions | Market & Consumption
.
The occurrence of drug resistance mechanisms usually involves a variety of signaling pathways related to tumor survival, such as cell metabolism, proliferation, and redox state, which greatly limits the means including chemotherapy and targeted therapy
.
Some originally sensitive tumors may also develop drug resistance due to new mutations after targeted therapy for a period of time
.
Therefore, people are trying to find the common "weakness" of different cancer targets and develop a single treatment method for this "weakness", so as to overcome the resistance of tumor treatment
.
In recent years, cellular reactive oxygen species (ROS) have been found to be abnormally elevated in tumor cells, and are closely related to glycolysis, redox, and proliferation signal transduction, indicating that it may be this shared "weakness
.
"
Previously, researchers have been able to use a gas discharge technology-low temperature atmospheric plasma (CAP) to generate exogenous ROS
.
CAP has been approved by the FDA as a catheter-guided scalpel for routine tumor and neurosurgery operations, and has shown efficacy in clinical trials for head and neck cancer
.
In 2021, a research team from Xi’an Jiaotong University, Old Dominion University, and the University of Utah found that in a drug-resistant mouse model of chronic myelogenous leukemia (CML), the CAP treatment program developed by it can effectively block oxidation, including oxidation.
Three cancer survival-related pathways, including imbalance of reduction, glycolysis and cell proliferation, are restored, so the program is named Trident CAP (Tri-CAP)
.
Tri-CAP can also cause high-efficiency apoptosis of CML and primitive CD34+ hematopoietic stem and progenitor cells, but at the same time it has little effect on non-malignant control cells.
Its good performance in animal experiments also brings about overcoming the problem of drug resistance in leukemia The dawn
.
The research results will be published in the latest PNAS on December 21, 2021
.
Research results (Source: PNAS Magazine) The main problem with existing ROS therapy is that the effective concentration of ROS cannot be determined: too low a ROS level cannot induce apoptosis, and too high a level will activate the cancer-promoting HIF-α pathway
.
The team has overcome this problem well.
They used a plasma jet (speed 1.
9 L/min) to generate ROS in argon with an oxygen content of 3%, and the distance between the electrode and the cell culture medium was 30 mm
.
This CAP protocol can generate extremely low levels of ROS in cell-free media, which are far lower than the ROS levels required to activate the HIF-α pathway.
At the same time, the temperature, pH and other indicators of the media are almost unaffected
.
In normal cells, imatinib-resistant CML cells (BCR-ABLT315I cells) and imatinib-sensitive CML cells (BCR-ABLp210 cells), Tri-CAP can cause drug-resistant cells to produce abnormally low levels The transients of extracellular and intracellular ROS increased sharply, achieving selective lethality to drug-resistant cell lines
.
Tri-CAP treatment of cell-free medium (Source: PNAS Magazine) After Tri-CAP treatment, drug-resistant CML cells had higher levels of ROS (Source: PNAS Magazine).
Researchers further discovered that Tri-CAP stimulated low levels of ROS Break the redox balance in the cell
.
In the BCR-ABL1+ cell line, Tri-CAP disrupts the redox balance in two ways: excessive intracellular ROS production and weakened antioxidant defense
.
On the contrary, normal cells in the control group can quickly restore the redox balance after three times of the same treatment
.
After Tri-CAP treatment, the redox imbalance between drug-resistant and sensitive CML cells (source: PNAS) also found that Tri-CAP can also inhibit multiple key targets in tumor metabolism and reduce lactic acid production
.
It was found in drug-resistant BCR-ABLT315I cells that the protein expression levels of many key molecules in aerobic glycolysis, such as PKM2, HK1, HK2 and PDK1, gradually decreased within 0-48 hours after Tri-CAP treatment, HK1 Almost completely missing
.
After Tri-CAP treatment, drug-resistant CML glycolysis is inhibited (Source: PNAS Magazine) Lactic acid, a product of aerobic glycolysis, is one of the activators of the main tumor proliferation pathway PI3K/AKT/mTOR.
The team further tested this The effect of a therapy on the pathway, it was found that the molecular markers activated by the pathway, such as phosphorylated mTOR and phosphorylated AKT, were significantly reduced in drug-resistant CML cell lines, while in sensitive CML cell lines and control cells The increase in expression of HIF-α in tumors promotes a similar pattern in the expression level of tumor resistance
.
After Tri-CAP treatment, the drug-resistant CMLAKT/mTOR/HIF-1α pathway is activated (Source: PNAS Magazine).
In short, these results indicate that Tri-CAP can preferentially block redox homeostasis, glycolysis, and glycolysis in resistant CML.
Proliferation (AKT/mTOR/HIF-1α), the three key ways of cancer survival, revealed for the first time a tumor treatment method that has not been reported before
.
In addition, Tri-CAP can also induce apoptosis of drug-resistant cells
.
CD34+ hematopoietic cells and progenitor cells of CML patients treated with Tri-CAP showed a high rate of apoptosis
.
In vivo experiments have also proved that these therapies can reduce tumor formation and improve the survival rate of tumor-bearing mice
.
Tri-CAP-treated tumor-bearing mice have reduced tumor growth and prolonged survival (Source: PNAS Magazine) Traditional ROS generation treatments, including radiotherapy, usually rely on high levels of ROS to induce direct cancer cell death, but at the same time the tumor The activation of survival-related pathways makes the therapeutic effect limited
.
In contrast, this research cleverly solves this problem and provides a basis for future clinical research
.
In general, Tri-CAP is expected to be a potential therapy to overcome and prevent the drug resistance of a variety of malignant tumors
.
End's selection of onlookers in the past, the more you exercise, the smarter you are! Nature: "Athlete's blood" can resurrect sedentary mice with blood! Sub-Journal of Rewen Nature: The age of human death may be calculated, the greater the pressure, the faster the aging process.
Nature sub-published two articles in a row: Cancer cells "dormant" for several years, or the key factors that lead to cancer metastasis/recurrence.
Hot article "Nature" publishes "Top Ten People of 2021"! The chief designer of China's "Tianwen No.
1" and the tracker of the new crown virus variants are all on the list.
Be alert! Cell Reports: Potential star anti-cancer targets may promote cancer? Does this target have a future? Medical immunotherapy| Biosimilars| Vaccines| Drug resistance| Drug targets| Healthy life| Pharmaceutical company news| Drug inventory| Pharmaceutical technology| Basic research on side effects of drugs/ Translational medicine leukemia| Lung cancer| Gastric cancer| Colorectal cancer| Liver cancer| Breast Cancer | Pancreatic Cancer | Cardiovascular Diseases | Neurodegenerative Diseases | Intestinal Microbial Medical Devices / Biotechnology In Vitro Diagnosis | Medical Devices | Bio-Nano | 3D Printing | Gene Testing | Single Cell Sequencing | Gene Editing | Assisted Reproduction | Artificial Intelligence | Precision medicine policy anti-cancer drugs | 4+7 volume procurement | Consumables | Filing system | Registrant system | Healthy China | New edition of basic medicine catalog | AI medical equipment | Telemedicine | Same-share market with different rights/capital IPO | Financing | Cooperation | Funds | Hong Kong Stock Exchange | Science and Technology Innovation Board | Growth Enterprise Market | R & D Investment | Acquisitions | Market & Consumption
