Conjugates of Cisplatin and Cyclooxygenase Inhibitors as Potent Antitumor Agents Overcoming Cisplatin Resistance

Cyclooxygenase‐2 (COX‐2) is an enzyme involved in tumorigenesis, and inhibitors of the enzyme are increasingly used as adjuvant modulators in anticancer therapies due to their synergistic effects with traditional chemotherapeutics. COX‐2 is also reported to cause resistance towards antitumor agents, such as cisplatin. Here, the first covalently linked conjugates of cisplatin and COX inhibitors are reported. These conjugates exhibit concerted transport of both drugs into tumor cells and simultaneous action upon intracellular cleavage. These platinum(IV) complexes show highly increased cytotoxicity compared with cisplatin and are even able to overcome cisplatin‐related resistance of tumor cells. While the results reported show that COX‐2 inhibition is not directly responsible for the potent activities of these conjugates, they do represent useful tool compounds for the elucidation of the influence of COX inhibitors on the efficacy of antitumor agents.

[1]  S. Lippard,et al.  Synthesis and characterization of Pt(IV) fluorescein conjugates to investigate Pt(IV) intracellular transformations. , 2013, Bioconjugate chemistry.

[2]  E. Wexselblatt,et al.  What do we know about the reduction of Pt(IV) pro-drugs? , 2012, Journal of inorganic biochemistry.

[3]  M. Jakupec,et al.  Novel tetracarboxylatoplatinum(IV) complexes as carboplatin prodrugs. , 2012, Dalton transactions.

[4]  M. I. Setyawati,et al.  Tuning the activity of platinum(IV) anticancer complexes through asymmetric acylation. , 2012, Journal of medicinal chemistry.

[5]  S. Lippard,et al.  Redox activation of metal-based prodrugs as a strategy for drug delivery. , 2012, Advanced drug delivery reviews.

[6]  Michael M Gottesman,et al.  Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes , 2012, Pharmacological Reviews.

[7]  L. Galluzzi,et al.  Molecular mechanisms of cisplatin resistance , 2012, Oncogene.

[8]  Justin J. Wilson,et al.  Synthesis, characterization, and cytotoxicity of platinum(IV) carbamate complexes. , 2011, Inorganic chemistry.

[9]  Jian-Hua Fu,et al.  Celecoxib Antagonizes the Cytotoxicity of Cisplatin in Human Esophageal Squamous Cell Carcinoma Cells by Reducing Intracellular Cisplatin Accumulation , 2011, Molecular Pharmacology.

[10]  R. Gust,et al.  Synthesis and biological activities of transition metal complexes based on acetylsalicylic acid as neo-anticancer agents. , 2010, Journal of medicinal chemistry.

[11]  Shonagh Walker,et al.  The status of platinum anticancer drugs in the clinic and in clinical trials. , 2010, Dalton transactions.

[12]  Lawrence J Marnett,et al.  Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents. , 2010, Cancer research.

[13]  S. Mandal,et al.  COX-2 as a target for cancer chemotherapy , 2010, Pharmacological reports : PR.

[14]  L. Marnett,et al.  Differential Sensitivity and Mechanism of Inhibition of COX-2 Oxygenation of Arachidonic Acid and 2-Arachidonoylglycerol by Ibuprofen and Mefenamic Acid† , 2009, Biochemistry.

[15]  L. Marnett The COXIB experience: a look in the rearview mirror. , 2009, Annual review of pharmacology and toxicology.

[16]  Heather R. Roberts,et al.  The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. , 2009, Carcinogenesis.

[17]  M. Jakupec,et al.  Novel bis(carboxylato)dichlorido(ethane-1,2-diamine)platinum(IV) complexes with exceptionally high cytotoxicity. , 2008, Journal of inorganic biochemistry.

[18]  G. Peters,et al.  Interaction between celecoxib and docetaxel or cisplatin in human cell lines of ovarian cancer and colon cancer is independent of COX-2 expression levels. , 2008, Biochemical pharmacology.

[19]  M. Jakupec,et al.  Novel di- and tetracarboxylatoplatinum(IV) complexes. Synthesis, characterization, cytotoxic activity, and DNA platination. , 2007, Journal of medicinal chemistry.

[20]  Zhiqiang Shen,et al.  Copper-aspirin complex inhibits cyclooxygenase-2 more selectively than aspirin. , 2007, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[21]  D. Stewart,et al.  Mechanisms of resistance to cisplatin and carboplatin. , 2007, Critical reviews in oncology/hematology.

[22]  Yiwei Li,et al.  Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. , 2007, Mini reviews in medicinal chemistry.

[23]  M. Dolan,et al.  Molecular mechanisms of resistance and toxicity associated with platinating agents. , 2007, Cancer treatment reviews.

[24]  G. Kucera,et al.  Cyclooxygenase inhibition and hyperthermia for the potentiation of the cytotoxic response in ovarian cancer cells. , 2007, Gynecologic oncology.

[25]  B. Erovic,et al.  Inhibition of cytotoxicity of cisplatin by cyclooxygenase-2 inhibitor nimesulide in head and neck cancer cell lines. , 2005, Oncology reports.

[26]  L. Juillerat-Jeanneret,et al.  Synthesis and characterization of platinum(IV) anticancer drugs with functionalized aromatic carboxylate ligands: influence of the ligands on drug efficacies and uptake. , 2005, Journal of medicinal chemistry.

[27]  I. Cree,et al.  Rapid up-regulation of cyclooxygenase-2 by 5-fluorouracil in human solid tumors , 2005, Anti-cancer drugs.

[28]  S. Byun,et al.  Augmentation of cisplatin sensitivity in cisplatin‐resistant human bladder cancer cells by modulating glutathione concentrations and glutathione‐related enzyme activities , 2005, BJU international.

[29]  J. Hayakawa,et al.  Mechanisms of platinum drug resistance. , 2005, Trends in pharmacological sciences.

[30]  C. S. Allardyce,et al.  Rational design of platinum(IV) compounds to overcome glutathione-S-transferase mediated drug resistance. , 2005, Journal of the American Chemical Society.

[31]  R. Botting,et al.  Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition , 2004, Pharmacological Reviews.

[32]  E. Martinelli,et al.  Prognostic Role of the Ratio between Cyclooxygenase-2 in Tumor and Stroma Compartments in Cervical Cancer , 2004, Clinical Cancer Research.

[33]  D. Elder,et al.  The cyclooxygenase 2-selective inhibitor NS398 inhibits proliferation of oral carcinoma cell lines by mechanisms dependent and independent of reduced prostaglandin E2 synthesis. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  M. Hall,et al.  Platinum(IV) antitumour compounds: their bioinorganic chemistry , 2002 .

[35]  N. Maggiano,et al.  Increased cyclooxygenase-2 (COX-2) expression is associated with chemotherapy resistance and outcome in ovarian cancer patients. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[36]  N. Maggiano,et al.  Increased cyclooxygenase-2 expression is associated with chemotherapy resistance and poor survival in cervical cancer patients. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  S. Grösch,et al.  COX‐2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX‐2 inhibitor celecoxib , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  K. Hattori,et al.  Synergistic effect of indomethacin with adriamycin and cisplatin on tumor growth. , 2001, Biological & pharmaceutical bulletin.

[39]  J. Essigmann,et al.  Mechanisms of resistance to cisplatin. , 2001, Mutation research.

[40]  S. Minoura,et al.  Indomethacin increases the cytotoxicity of cis-platinum and 5-fluorouracil in the human uterine cervical cancer cell lines SKG-2 and HKUS by increasing the intracellular uptake of the agents , 2001, International Journal of Clinical Oncology.

[41]  L. Marnett,et al.  Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. , 2000, Journal of medicinal chemistry.

[42]  J. Reedijk,et al.  Can Pt(IV)—amine complexes act as ‘prodrugs’? , 1998 .

[43]  Sunhee Choi,et al.  Reduction and Anticancer Activity of Platinum(IV) Complexes , 1998 .

[44]  L. Kèlland,et al.  Metabolism, protein binding and in vivo activity of the oral platinum drug JM216 and its biotransformation products. , 1996, Anticancer research.

[45]  M. Galanski,et al.  Carboxylation of Dihydroxoplatinum(IV) Complexes via a New Synthetic Pathway. , 1996, Inorganic chemistry.

[46]  R. Perez,et al.  Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule. , 1994, Cancer research.

[47]  L. Kèlland,et al.  Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-cyclohexylamine platinum(IV): an orally active platinum drug. , 1993, Cancer research.

[48]  L. Kèlland,et al.  Comparison of cellular accumulation and cytotoxicity of cisplatin with that of tetraplatin and amminedibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) in human ovarian carcinoma cell lines. , 1992, Cancer research.

[49]  E. Pettersen,et al.  The binding of cis-dichlorodiammineplatinum(II) to extracellular and intracellular compounds in relation to drug uptake and cytotoxicity in vitro. , 1992, British Journal of Cancer.

[50]  H. Earl,et al.  A randomized trial of carboplatin versus iproplatin in untreated advanced ovarian cancer. , 1991, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  R. Lange,et al.  Clinical and pharmacological studies with cis-diamminedichloroplatinum (II). , 1973, Cancer research.

[52]  M. Jakupec,et al.  Tuning of lipophilicity and cytotoxic potency by structural variation of anticancer platinum(IV) complexes. , 2011, Journal of inorganic biochemistry.

[53]  C. Tsatsanis,et al.  Signalling networks regulating cyclooxygenase-2. , 2006, The international journal of biochemistry & cell biology.

[54]  B. Sikic,et al.  Pharmacokinetics and protein binding of cis-dichlorodiammine platinum (II) administered as a one hour or as a twenty hour infusion , 2004, Cancer Chemotherapy and Pharmacology.

[55]  T. Kuczek,et al.  Cisplatin versus cisplatin combined with piroxicam in a canine model of human invasive urinary bladder cancer , 2000, Cancer Chemotherapy and Pharmacology.

[56]  K. Lemma,et al.  Kinetics and mechanism for reduction of oral anticancer platinum(IV) dicarboxylate compounds by L-ascorbate ions , 2000 .

[57]  T. Hambley,et al.  The Influence of the Axial Ligands of a Series of Platinum(IV) Anti-Cancer Complexes on Their Reduction to Platinum(II) and Reaction With DNA , 1995 .

[58]  W. Mason Platinum(ii)-catalyzed substitutions of platinum(iv) complexes , 1972 .