Molecular basis of cellular response to cisplatin chemotherapy in non-small cell lung cancer (Review)
TL;DR: In this review, insights are provided into the pathways involved in cisplatin damage from entering the cells to execution of apoptosis or survival of NSCLC cells and this knowledge should provide a basis for further studies to improve the understanding of molecular events associated with lung cancer.
Abstract: Cisplatin is one of the most potent anticancer agents, displaying significant clinical activity against a variety of solid tumors. For more than two decades, the most effective systemic chemotherapy for non-small cell lung cancer (NSCLC), the leading cause of cancer morbidity and mortality among men and women in the western world, was cisplatin-based combination treatment. Unfortunately, the outcome of cisplatin therapy on NSCLC seems to have reached a plateau. Therefore, the biological mechanisms of cisplatin action need to be understood in order to overcome the treatment plateau on NSCLC. Moreover, the development of resistance is a hurdle in the use of this drug. The molecular mechanisms that underlie this chemoresistance are largely unknown. Possible mechanisms of acquired resistance to cisplatin include reduced intracellular accumulation of cisplatin, enhanced drug inactivation by metallothionine and glutathione, increased repair activity of DNA damage, and altered expression of oncogenes and regulatory proteins. In addition, it is generally accepted that cytotoxicity of cisplatin is mediated through induction of apoptosis and arrest of cell cycle resulting from its interaction with DNA, such as the formation of cisplatin-DNA adducts, which activates multiple signaling pathways, including those involving p53, Bcl-2 family, caspases, cyclins, CDKs, pRb, PKC, MAPK and PI3K/Akt. Increased expression of anti-apoptotic genes and mutations in the intrinsic apoptotic pathway may contribute to the inability of cells to detect DNA damage or to induce apoptosis. Towards an understanding of the molecular basis of the cellular response to cisplatin-based chemotherapy in NSCLC, in this review we provide some insights into the pathways involved in cisplatin damage from entering the cells to execution of apoptosis or survival of NSCLC cells. We believe that as more and more molecular mechanisms of response to cisplatin-based therapy are unraveled, this knowledge should provide a basis for further studies to improve our understanding of molecular events associated with lung NSCLC as well as to devise novel and effective therapeutic approaches to overcome the treatment plateau or reverse drug resistance in this disease.
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TL;DR: The typical cancer‐drug‐delivery process of an intravenously administered nanomedicine is analyzed and it is concluded that the delivery involves a five‐step CAPIR cascade and that high efficiency at every step is critical to guarantee high overall therapeutic efficiency.
Abstract: Current cancer nanomedicines can only mitigate adverse effects but fail to enhance therapeutic efficacies of anticancer drugs. Rational design of next-generation cancer nanomedicines should aim to enhance their therapeutic efficacies. Taking this into account, this review first analyzes the typical cancer-drug-delivery process of an intravenously administered nanomedicine and concludes that the delivery involves a five-step CAPIR cascade and that high efficiency at every step is critical to guarantee high overall therapeutic efficiency. Further analysis shows that the nanoproperties needed in each step for a nanomedicine to maximize its efficiency are different and even opposing in different steps, particularly what the authors call the PEG, surface-charge, size and stability dilemmas. To resolve those dilemmas in order to integrate all needed nanoproperties into one nanomedicine, stability, surface and size nanoproperty transitions (3S transitions for short) are proposed and the reported strategies to realize these transitions are comprehensively summarized. Examples of nanomedicines capable of the 3S transitions are discussed, as are future research directions to design high-performance cancer nanomedicines and their clinical translations.
708 citations
TL;DR: The results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs and might be a potential target to enhance the effect of anticancers drugs.
Abstract: Purpose: NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, therefore, the role of Nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated. Experimental Design: We used three human lung cancer cell lines with different degrees of Nrf2 activation: Nrf2 was highly activated in A549 cells, slightly activated in NCI-H292 cells, and not activated in LC-AI cells under unstimulated conditions. Result: A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-AI cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA). The cell proliferation was also most prominently inhibited in A549 cells by treatment with Nrf2-siRNA. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. The degree of DNA crosslink and apoptosis after treatment with cisplatin was significantly elevated in A549 cells by Nrf2-siRNA. Knockdown of Nrf2 arrested the cell cycle at G 1 phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-AI cells. Conclusion: These results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs. Thus, Nrf2 might be a potential target to enhance the effect of anticancer drugs.
377 citations
Soochow University (Suzhou)1, Chinese Academy of Sciences2, Center for Excellence in Education3, University of Science and Technology of China4, Wuhan University5, Zhejiang University6, National Institutes of Health7, Hunan University8, Nanjing University9, Xiamen University10, Tsinghua University11, Huazhong University of Science and Technology12, University of Florida13
TL;DR: The recent advances of intelligent cancer nanomedicine are demonstrated, and the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanotechine including various imaging and therapeutic applications, as well as nanotoxicity is discussed.
Abstract: Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.
316 citations
TL;DR: A cancer‐cell targeted nuclear‐localization polymer–drug conjugate has been developed by introducing folic‐acid targeting groups and an anticancer drug camptothecin to PLL/amide (FA‐PLL/ ammonia‐CPT), which efficiently enters folate‐receptor overexpressed cancer cells and traverses to their nuclei.
Abstract: DNA-toxin anticancer drugs target nuclear DNA or its associated enzymes to elicit their pharmaceutical effects, but cancer cells have not only membrane-associated but also many intracellular drug-resistance mechanisms that limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug-resistance barriers. The cationic polymer poly(L-lysine) (PLL) is capable of nuclear localization and may be used as a drug carrier for nuclear drug delivery, but its cationic charges make it toxic and cause problems in in-vivo applications. Herein, PLL is used to demonstrate a pH-triggered charge-reversal carrier to solve this problem. PLL's primary amines are amidized as acid-labile β-carboxylic amides (PLL/amide). The negatively charged PLL/amide has a very low toxicity and low interaction with cells and, therefore, may be used in vivo. But once in cancer cells' acidic lysosomes, the acid-labile amides hydrolyze into primary amines. The regenerated PLL escapes from the lysosomes and traverses into the nucleus. A cancer-cell targeted nuclear-localization polymer–drug conjugate has, thereby, been developed by introducing folic-acid targeting groups and an anticancer drug camptothecin (CPT) to PLL/amide (FA-PLL/amide-CPT). The conjugate efficiently enters folate-receptor overexpressing cancer cells and traverses to their nuclei. The CPT conjugated to the carrier by intracellular cleavable disulfide bonds shows much improved cytotoxicity.
279 citations
TL;DR: It is suggested that silymarin significantly attenuated the hepatotoxicity as an indirect target ofCDDP in an animal model of CDDP-induced nephrotoxicity.
Abstract: Cisplatin (CDDP) is a widely used anticancer drug, but at high dose, it can produce undesirable side effects such as hepatotoxicity. Because silymrin has been used to treat liver disorders, the protective effect of silymarin on CDDP -induced hepatotoxicity was evaluated in rats. Hepatotoxicity was determined by changes in serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST], nitric oxide [NO] levels, albumin and calcium levels, and superoxide dismutase [SOD], glutathione peroxidase [GSHPx] activities, glutathione content, malondialdehyde [MDA] and nitric oxide [NO] levels in liver tissue of rats. Male albino rats were divided into four groups, 10 rats in each. In the control group, rats were injected i.p. with 0.2 ml of propylene glycol in saline 75/25 (v/v) for 5 consecutive days [Silymarin was dissolved in 0.2 ml of propylene glycol in saline 75/25 v/v]. The second group were injected with CDDP (7.5 mg /kg, I.P.), whereas animals in the third group were i.p. injected with silymarin at a dose of 100 mg/kg/day for 5 consecutive days. The Fourth group received a daily i.p. injection of silymarin (100 mg/kg/day for 5 days) 1 hr before a single i.p. injection of CDDP (7.5 mg/kg). CDDP hepatotoxicity was manifested biochemically by an increase in serum ALT and AST, elevation of MDA and NO in liver tissues as well as a decrease in GSH and the activities of antioxidant enzymes, including SOD, GSHPx in liver tissues. In addition, marked decrease in serum NO, albumin and calcium levels were observed. Serum ALT, AST, liver NO level, MDA was found to decreased in the combination group in comparison with the CDDP group. The activities of SOD, GSHPx, GSH and serum NO were lower in CDDP group than both the control and CDDP pretreated with silymarin groups. The results obtained suggested that silymarin significantly attenuated the hepatotoxicity as an indirect target of CDDP in an animal model of CDDP-induced nephrotoxicity.
255 citations
Cites background from "Molecular basis of cellular respons..."
...Cisplatin [cis-diamminechloroplatinum (II)] (CDDP) is a potent antineoplastic agent used for the treatment of a wide range of cancers (Saad et al., 2004; Wang et al., 2004)....
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References
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TL;DR: The start: platinum complexes for the treatment of cancer - why the search goes on and new developments: structure-activity relationships within di- and trinuclear platinum phase I clinical anticancer agents the development of orally-active platinum drugs methods for screening the potential antitumor activity of platinum compounds in combinatorial libraries computational studies on platinum antitumors complexes and their adducts with nucleid acids constituents.
Abstract: Part I The start: platinum complexes for the treatment of cancer - why the search goes on Part II Cisplatin - how good is it?: clinical status of cisplatin and other PT antitumor drugs Part III How does it possibly work? - biochemistry: the response of cellular proteins to cisplatin - damaged DNA the mechanism of action of cisplatin - from adducts to apoptosis replication of platinated DNA and its mutagenic consequences interstand cross-links in cisplatin- or transplatin-modified DNA Part IV Chemistry relevant to PT-biomolecule interactions: platinum complexes - hydrolysis and binding to N7 and N1 of purines reactivity and inertness of PT-nucleobase complexes kinetics and selectivity of DNA platination structure and dynamics of PT anticancer drug adducts from nucleotides to oligonucleotides as revealed by NMR methods 195Pt and 15N NMR spectroscopic studies of cisplatin reactions with biomolecules structural aspects of PT-purine interactions - from models to DNA platinum-sulfur interactions involved in antitumor drugs, rescue agents and biomolecules diammine- and diamineplatinum complexes with non-sulfur-containing amino acids and peptides Part V Inorganic chemistry revived or initiated by cisplatin: platinum blues - on the way toward unraveling a mystery heteronuclear PT(II) complexes with pyrimidine nucleobases displatinum(III) complexes - chemical species more widely spread than suspected inorganic and organometallic chemistry of cisplatin-derived PT(III) complexes Part VI New developments: structure-activity relationships within di- and trinuclear platinum phase I clinical anticancer agents the development of orally-active platinum drugs methods for screening the potential antitumor activity of platinum compounds in combinatorial libraries computational studies on platinum antitumor complexes and their adducts with nucleid acids constituents
1,347 citations
Book•
01 Jan 1993
TL;DR: The cellular and molecular pharmacology of the anthrapyrazole antitumour agent and the mitomycins - natural cross-linkers of DNA, M.D. Wilson and F.A. Tomasz are studied.
Abstract: DNA topoisomerases, K. Kohn and R. Ralph the cellular and molecular pharmacology of the anthrapyrazole antitumour agent, D.R. Newell and L.H. Patterson calicheamicin, G.A. Elistad and W.D. Ding molecular pharmacology of intercalator - groove binder hybrid molecules, C. Bailly and J.P. Henichart bleomycins - mechanism of polynucleotide recognition and oxidative degradation, A. Natrajan and S.M. Hecht kinetic analysis of drug-nucleic acid binding modes - absolute rates and effects of salt concentration, W.D. Wilson and F.A. Tanions acridine-based anti-cancer drugs, W.A. Denny and B.C. Baguley the mitomycins - natural cross-linkers of DNA, M. Tomasz.
328 citations
TL;DR: New findings showing that the checkpoint kinase CHK2 regulates a crucial central player in checkpoint pathways-the tumor suppressor protein p53 are discussed.
Abstract: When the DNA of a cell is damaged, a network of proteins tell the cell to stop at the nearest cell cycle checkpoint so that the DNA repair machinery can set about shoring up the damage and the cell can decide whether to continue proliferating. In a Perspective, [Carr][1] discusses new findings ([ Hirao et al .][2]) showing that the checkpoint kinase CHK2 regulates a crucial central player in checkpoint pathways-the tumor suppressor protein p53.
[1]: http://www.sciencemag.org/cgi/content/full/287/5459/1765
[2]: http://www.sciencemag.org/cgi/content/full/287/5459/1824
117 citations