Eloxatin, 1r,2rcyclohexane1,2diamineethanedioatoo,oplatinumii formula. On the discovery, biological effects, and use of cisplatin and. The anticancer activity of cisplatin was discovered in the early 1960s by. Classical examples such as cisplatin, as well as very recent examples from the authors and other work, will be discussed in detail, and in the. Platinumbased drugs cisplatin, carboplatin and oxaliplatin are widely used in the therapy of human neoplasms. Pdf understanding and improving platinum anticancer drugs. Platinum chemotherapeutics are the most widely prescribed drugs in modern oncology administered to about 50 % of all cancer patients, either alone or in combination with other anticancer drugs andor radiation therapy. Platinum anticancer drugs since cisplatin, the first fda approved ptii anticancer drug, went on the market in 1978, platinum anticancer drugs have been a great success. Comparison of responsiveness to cancer development and. Platinumdna adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of. Immunotherapy is usually for treating melanoma, a dangerous form of skin cancer. Used for many of the same cancers and in similar regimens to cisplatin. Chemotherapy, surgery and radiation are the main treatments for cancer.
Wang d, lippard sjcellular processing of platinum anticancer drugs. Cellular mechanisms of activity, drug resistance and induced side effects. Three platinum compounds currently in use worldwidecisplatin, carboplatin, and oxaliplatin have been developed with crucial support from the u. The roles of copper transporters in cisplatin resistance. Review article molecular mechanisms of drug resistance. The major cellular processes by which cisplatin enters and attacks cancer cells include uptake and transport, formation of dna adducts and their. Different treatments have been applied to kill cancer cells such as chemotherapy, which is the use of chemicals or drugs in order to treat cancer cells. Medicinal plants in the prevention and treatment of colon. The segment for targeted drugs accounts for more than 40% of share value in.
To evaluate the differences in the anticancer reactivity between the injected llc cells and mouse stocks in a syngeneic mouse model using c57bl6n mice, the responsiveness to the anti. In recent years, this picture has increased in complexity, based on studies. The standard treatment for cancer is generally based on using cytotoxic drugs, radiotherapy, chemotherapy, and surgery. Cisplatin cddp is widely used to treat oral squamous cell carcinoma oscc, however, many patients exhibit acquired drug resistance. Anticancer drugs with minimum sideeffects driving growth in the market. These and other icbs are expected to obtain regulatory approval for an expanding panel of oncological indications. The platinumbased drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Despite tremendous efforts to conquer malignant diseases, the war on cancer declared by richard nixon four decades ago seems to be lost. Mechanistic work, including a crystal structure analysis of platinummodified dna in the active site of rna polymerase ii, is discussed herein. Jbic journal of biological inorganic chemistry 2005, 10 3, 305315. Cells were treated with various concentrations of ptacd or cispt, and viable cell number was determined by 34,5dimethylthiazol2yl2,5diphenol tetrazolium bromide. Combination of oxaliplatin and irinotecan on human colon. Request pdf wang d, lippard sjcellular processing of platinum anticancer drugs.
Such knowledge of the cellular processing of cisplatin adducts with dna provides valuable clues for the rational design of more efficient platinumbased drugs as well as the development of new therapeutic strategies. Platinum neurotoxicity pharmacogenetics pubmed central pmc. Understanding and improving platinum anticancer drugs ncbi. Their clinical success is, however, limited due to severe side effects and intrinsic or acquired resistance to the treatment. Its binding to dna prevents replication and transcription which causes cell death through apoptosis. Western michigan university, 2015 cancer is considered the second leading cause of death after heart attack. Dinuclear platinum anticancer complexes with fluorescent n,n. Cellular distribution and processing of platinumbased anticancer drugs, as described in the literature, vary significantly between different tumor types. The cellular target of the three fdaapproved platinum drugs, as well as many related compounds that have been investigated, is nuclear dna. A dissertation submitted in partial fulfillment of the requirements for the degree of doctor of philosophy in chemical biology at virginia commonwealth university. Nrf2 enhances cell proliferation and resistance to.
Copper transporters and the cellular pharmacology of the. Cellular processing of platinum anticancer drugs readcube. Sclc31a1 plays an important role in regulating copper homeostasis because copper is an essential micronutrient and copper deficiency is detrimental to many important cellular functions, but excess copper is toxic. Since binding and cleavage of dna is at the heart of cellular transcription and translation, it is an obvious target for therapeutic intervention and the development of diagnostic structural probes. At the cellular level, the chemotherapy interferes with dna replication and metabolic function of the neurons. Much effort has been put into the development of new platinum anticancer complexes, but none of them has reached worldwide clinical application so far. Some of the platinumbased antitumor drugs like cisplatin, carboplatin and oxaliplatin, have several disadvantages including side effects, cisplatinresistant tumors, limited solubility in aqueous media, and so on. Approximately 21,800 women in the us will be diagnosed with ovarian cancer in 2011. Metal coordination compounds with slow metalligand exchange rates, comparable to those of cell division processes, often appear to be highly active in killing cancer cell lines. While gsh deficiency, or a decrease in the gshglutathione disulphide gssg ratio, leads to an increased susceptibility to.
Platinum resistance in breast and ovarian cancer cell. Taiwan j obstet gynecol september 2009 vol 48 no 3 243 chemotherapeutic drug resistance in cancer therapy 12. Nfe2related factor 2 nrf2, a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. This is particularly marked in platinum and ruthenium complexes. Inorganic constructs such as cisplatin and its analogs exercise antitumor activity by innersphere coordination to dna. The process of translesion synthesis tls, is one mechanism by which cells can tolerate and survive platinuminduced dna. Researchers have now identified a way to enhance the in vitro.
There are many factors to determine cancer treatment including the stage of the. We used three human lung cancer cell lines with different degrees of nrf2 activation. Xanes determination of the platinum oxidation state distribution in cancer cells treated with platinumiv anticancer agents. B, immunoblot analysis of protein lysate from dld1 cells treated as described for a and probed for expression of total parp. Since there were clearly opposite interactions depending on the cell line, we further investigated cellular determinants possibly involved in the interaction between the two drugs in hct8 and sw620 cells.
Cisplatin is a chemotherapy medication used to treat a number of cancers. Enhancing the effects of platinumbased anticancer drugs date. Anticancer drug response of three different llcbearing c57bl6n stocks. The fate of platinumii and platinumiv anticancer agents in cancer cells and tumors. Cddp has clinical benefit for several types of solid tumors. Breast and ovarian cancers are among the 10 leading cancer types in females with mortalities of 15% and 6%, respectively. Platinumbased drugs have become a mainstay of cancer therapy. Carboplatin 1,1cyclobutyldicarboxylate is one of the main platinumbased drug. Glutathione gsh plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in gsh homeostasis are involved in the etiology and progression of many human diseases including cancer.
Cisplatin cisdiamine dichloroplatinum ii is a platinumbased anticancer drug widely used for the treatment of many solid tumors. Understanding and improving platinum anticancer drugs. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma. Immunotherapy for ovarian cancer cancer research institute. Yesassociated protein yap is a transcriptional coactivator of the hippo pathway that regulates organ size and promotes cell proliferation. Drugs such as 5fu and cpt11 must be converted to their active metabolites to exert their anticancer effects. Platinum dna adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. Cisplatin, carboplatin and oxaliplatin are platinumbased drugs that are widely used in cancer chemotherapy.
It is given by injection into a vein common side effects include bone marrow suppression, hearing problems, kidney problems. Semantic scholar extracted view of cytotoxicity of platinum anticancer drugs in mammalian cell lines of metastatic cancer by hosannah evie. Enhancing the effects of platinumbased anticancer drugs. New platinum anticancer drugs the possibilities of improved selectivity work is. Cellbased assays reveal altered cellular uptake properties and a cancer cellkilling profile different from those of established platinum drugs. Resveratrol may reduce oxidative stress induced by. Irinotecan slowed down the early platinumdna adducts repair 1 h after oxaliplatin exposure in the presence of irinotecan only in hct8 cells p0. Use of cisplatin and metallocenes in anticancer chemotherapy.
Resveratrol decreased the production of 8epiprostaglandin f2 a biomarker of lipid peroxidation in control blood platelets and platelets treated with platinum compounds 10. The hippo pathway transcriptional coactivator, yap. The aim of the present work was to provide an overview of medicinal plants effective on colon cancer with special emphasis on bioactive components and underlying mechanisms of action. The aquatedactivated platinum complexes can react with nucleophilic centers on purine bases of dna, particularly the n7 positions of guanosine and adenosine residues. Nucleotide excision repair from a sitespecifically platinummodified nucleosome. Pdf characterization and cellular uptake of platinum. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to dna. Cellular interactions of platinum drugs request pdf. These drugs are used to treat almost half of people receiving chemotherapy for cancer. Alterations by antidepressants and heparan sulfate proteoglycans by brigitte j engelmann, b. Despite the pervasiveness of platinum drugs in cancer. Indeed recent work implied that the cellular copper machinery may be involved in cisplatin cell export and drug resistance. Synthesis of new platinumbased anticancer drugs yasser saud. Roles of micrornas in the resistance to platinum based.
Impact of stat3 phosphorylation on the clinical effectiveness of antiegfrbased therapy in patients with metastatic colorectal cancer. Wang d, lippard sjcellular processing of platinum anticancer. Despite the pervasiveness of platinum drugs in cancer treatment regimens. The platinum drugs appear to effect the axons, myelin sheath, neuronal cell body and the glial structures of the neurons. In this form of chemotherapy, popular drugs include cisplatin, oxaliplatin, and carboplatin, but several have been proposed or are under development.
In this study, therefore, the role of nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated. The resurgence of platinumbased cancer chemotherapy. Recent research has revealed that human copper homeostasis is tightly controlled by interregulatory circuitry involving copper, sp1, and. Chemistry and biochemistry of a leading anticancer drug. Cellular processing of platinum anticancer drugs nature. Metalligand exchange kinetics in platinum and ruthenium.
Platinumbased antineoplastic drugs informally called platins are chemotherapeutic agents used to treat cancer. National cancer institute nci, including screening by the 60cell line panel nci60 screen of nci. Multiple lines of evidence indicate that the platinumcontaining cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The widespread use of platinum agents in the treatment of cancer began with the discovery of the antineoplastic activity of cisplatin by barnett rosenberg in the 1960s. This process, together with the nci compare program, identified clear differences in activity profiles and. Platinum drugs, anticancer, side effects, cellular uptake, molecular orbital computations abstract the side effects of pt drugs have been examined by evaluating the literature on pt chemistry, pharmacology, cellular transport, and clinical efficacy and correlating these studies with molecular orbital computations. However, the use of traditional treatments has received attention in recent years. A major sideeffect of platinumbased anticancer drugs is damage to. Pt anticancer drugs, ptdna ptprotein adducts, cellular toxicity, free radicals. Drug delivery systems with tumortargeting potential are highly desired.
Cpt11 is converted to sn38 by carboxylesterase ce 30, and several in vitro studies have indicated that the level of ce activity in cancer cells is an important determinant of cpt11 sensitivity. Platinum anticancer drugs, chemical biology of chemical. The six platinum anticancer drugs with marketing approval for the treatment of human and animal tumors. Interaction of cisplatin and dnatargeted 9aminoacridine. Mechanisms of chemotherapeutic drug resistance in cancer. Clinical application of platinum based anticancer drugs is largely limited by severe general toxicity and drug resistance. Based on therapy, the anticancer drug market is segmented into immunotherapy, targeted therapy and chemotherapy. Platinumdna adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. Lippardcellular processing of platinum anticancer drugs. Cellbased assays reveal altered cellular uptake properties and a cancer.
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