Cancer is one of the most common public health threats of the 21st century. It is a clinically diverse set of diseases affecting multicellular organisms that can appear in various phenotypes. Such diseases are caused by the accumulation of numerous genetic alterations in the cell, resulting in chang...
Cancer is one of the most common public health threats of the 21st century. It is a clinically diverse set of diseases affecting multicellular organisms that can appear in various phenotypes. Such diseases are caused by the accumulation of numerous genetic alterations in the cell, resulting in changes in gene expression patterns. There are three main routes of treatment to treat cancer: surgery, radiation therapy, and chemotherapy. Chemotherapy is used to reduce the size of cancer cells prior to surgery and radiation therapy. It is also used to prevent recurrence of cancer cells after surgery and radiation therapy. Chemotherapy is also used in palliative care for patients with terminal cancer to prolong survival and relieve symptoms. Above all, unlike surgery and radiotherapy, chemotherapy has the advantage of affecting the whole body through systemic delivery. Therefore, it is used for metastatic treatment in patients who are thought to have a potential for secondary growth but have not yet progressed clinically. Among chemotherapy drugs widely used for cancers, cisplatin is one of the most compelling drugs. Cisplatin, in its neutral state, passively diffuses across a cellular lipid bilayer, which is impermeable to charged particles. Since the intracellular concentration of Cl− is less than one tenth of its extracellular value, cisplatin becomes hydrolyzed into monovalent or divalent cations by releasing Cl− upon cell entry. The cationic state of cisplatin, which accumulates inside a cell, is the active form that binds to DNA. However, other anionic species such as carbonates, phosphates, and thiolates that are common inside cells are also known to interfere with cisplatin. Another important factor that deserves due attention is the complexity originating from packaging of DNA into chromatin, the form that cellular DNA adopts. Recent studies emphasized multi-faceted involvements of chromatin in various events triggered by cisplatin. Therefore, we have studied the effect of cisplatin on the nucleosomal DNA, as a chemotherapeutic subject, under physiological salt condition. To that end, we improved the magnetic tweezers and achieved nanometer resolution. Nucleosomal DNA was also prepared in vitro using Nucleosome Assembly Protein 1 (NAP1). Using this, we were able to directly observe changes in nucleosomal DNA due to physical forces or salts at high concentrations. We then treated the nucleosomal DNA with cisplatin in a physiological solution. When mechanical force or charge screening effects were applied to cisplatin treated nucleosomal DNA, we surprisingly observed suppression of core histone relaxation from DNA binding sites even a low concentration of cisplatin.
Since chromatin is the basic setting for various genetic events and thus plays important roles in cellular metabolism, we tested another drug implicated to interfere with chromatin metabolism in the opposite way by destabilizing chromatin and nucleosome core particle. The drug is a curaxin, which has been known to simultaneously activate p53, inhibit NF-kB, and cause death of various tumor cells. It has also been shown that curaxin binds directly to DNA but does not damage DNA. According to a recent speculation about the effect of curaxin on chromatin and nucleosomal DNA, we tested it and found that the chromatin structure was destroyed and that the physical properties of curaxin-treated DNA was dramatically changed. This effect could disrupt various cellular processes and eventually cause cell death.
The mechanistic details gained at single molecule level clarify the mechanism for the anti-cancer effect of chemotherapy drugs and confirm that the nucleosomal DNA is indeed effective as a drug target. This will be beneficial to designing a new generation of anti-cancer drugs.
Cancer is one of the most common public health threats of the 21st century. It is a clinically diverse set of diseases affecting multicellular organisms that can appear in various phenotypes. Such diseases are caused by the accumulation of numerous genetic alterations in the cell, resulting in changes in gene expression patterns. There are three main routes of treatment to treat cancer: surgery, radiation therapy, and chemotherapy. Chemotherapy is used to reduce the size of cancer cells prior to surgery and radiation therapy. It is also used to prevent recurrence of cancer cells after surgery and radiation therapy. Chemotherapy is also used in palliative care for patients with terminal cancer to prolong survival and relieve symptoms. Above all, unlike surgery and radiotherapy, chemotherapy has the advantage of affecting the whole body through systemic delivery. Therefore, it is used for metastatic treatment in patients who are thought to have a potential for secondary growth but have not yet progressed clinically. Among chemotherapy drugs widely used for cancers, cisplatin is one of the most compelling drugs. Cisplatin, in its neutral state, passively diffuses across a cellular lipid bilayer, which is impermeable to charged particles. Since the intracellular concentration of Cl− is less than one tenth of its extracellular value, cisplatin becomes hydrolyzed into monovalent or divalent cations by releasing Cl− upon cell entry. The cationic state of cisplatin, which accumulates inside a cell, is the active form that binds to DNA. However, other anionic species such as carbonates, phosphates, and thiolates that are common inside cells are also known to interfere with cisplatin. Another important factor that deserves due attention is the complexity originating from packaging of DNA into chromatin, the form that cellular DNA adopts. Recent studies emphasized multi-faceted involvements of chromatin in various events triggered by cisplatin. Therefore, we have studied the effect of cisplatin on the nucleosomal DNA, as a chemotherapeutic subject, under physiological salt condition. To that end, we improved the magnetic tweezers and achieved nanometer resolution. Nucleosomal DNA was also prepared in vitro using Nucleosome Assembly Protein 1 (NAP1). Using this, we were able to directly observe changes in nucleosomal DNA due to physical forces or salts at high concentrations. We then treated the nucleosomal DNA with cisplatin in a physiological solution. When mechanical force or charge screening effects were applied to cisplatin treated nucleosomal DNA, we surprisingly observed suppression of core histone relaxation from DNA binding sites even a low concentration of cisplatin.
Since chromatin is the basic setting for various genetic events and thus plays important roles in cellular metabolism, we tested another drug implicated to interfere with chromatin metabolism in the opposite way by destabilizing chromatin and nucleosome core particle. The drug is a curaxin, which has been known to simultaneously activate p53, inhibit NF-kB, and cause death of various tumor cells. It has also been shown that curaxin binds directly to DNA but does not damage DNA. According to a recent speculation about the effect of curaxin on chromatin and nucleosomal DNA, we tested it and found that the chromatin structure was destroyed and that the physical properties of curaxin-treated DNA was dramatically changed. This effect could disrupt various cellular processes and eventually cause cell death.
The mechanistic details gained at single molecule level clarify the mechanism for the anti-cancer effect of chemotherapy drugs and confirm that the nucleosomal DNA is indeed effective as a drug target. This will be beneficial to designing a new generation of anti-cancer drugs.
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#single molecule anti-cancer drugs
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