Abstract
Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antiproliferative performance on a panel of human tumor cell lines, including a malignant pleural mesothelioma (MPM) one, a very chemoresistant tumor. The main reason of the increased activity relies on the enhanced lipophilicity of these Pt(IV) conjugates that in turn promotes increased cellular accumulation. A quick Pt(IV)→Pt(II) reduction generates the active cisplatin metabolite. The NSAID adjuvant action seems to be almost independent from cyclooxygenase-2 (COX-2) expression in the tumor cells under investigation (lung A-549, colon HT-29, HCT 116, SW480, ovarian A2780, and biphasic MPM MSTO-211H), but it seems to rely (at least in part) on the activation of the NSAID activated gene, NAG-1 (a member of the transforming growth factor beta, TGF-β, superfamily), which has been suggested to be involved in NSAID antiproliferative activity.
Highlights
The non-steroidal anti-inflammatory drugs (NSAIDs) adjuvant action seems to be almost independent from cyclooxygenase-2 (COX-2) expression in the tumor cells under investigation, but it seems to rely on the activation of the NSAID activated gene, NAG-1, which has been suggested to be involved in NSAID antiproliferative activity
There are two main problems when a single drug is used in clinics: (i) There is no pharmacological agent with a “perfect” selectivity; (ii) even the most successful therapies may lose potency with time because of the development of acquired resistance
The development of a cisplatin-based combination chemotherapy such as the PVB protocol in the late 1970s resulted in a dramatic improvement in the prognosis of patients with metastatic germ cell tumors, and overall cure rates exceeded 80%
Summary
There are two main problems when a single drug is used in clinics: (i) There is no pharmacological agent with a “perfect” selectivity (and this causes systemic toxicity); (ii) even the most successful therapies may lose potency with time because of the development of acquired resistance. At the same time, when two or more drugs which have different biochemical mechanisms of action are combined, the probability of selecting tumor cells resistant to all the drugs is reduced. These considerations apply to Pt-based anticancer compounds, the prototype of which is cisplatin ((SP-4-2)-diamminedichloridoplatinum(II) and cis-[PtCl2(NH3)2]) [1]. MInolt.hSeci.p2r0e1s9e, 2n0t, w307o4rk, two complexes containing axial ketoprofen (2-(3-benzoylphenyl)propa3nofo1i8c acid) or naproxen (2-(6-methoxynaphthalen-2-yl)propanoic acid) (Figure 2) were synthesized and tested for their biological features against a panel of human cancer cell lines. AFilnlaltlhy,eascaomrefpelreexnecse cwomerpeoucnhdar,a1cwteariszpedrepwariethd, arcecvoerrdsiendg-ptohathsee phroigchedupreerrfoeprmoratnedcebyliDquhiadr ceht raolm., abtyogreraapcthinyg(R(OP-CH-6P-L4C4))-dcoiaumplmedinweditihchelloercitdroosdpirhayydiroonxiizdaotpiolnat-imnuasms (sIpVe)ctwroitmhetthrye (aEnShIy-MdrSid) eanodf macuetlytilnsualcilceyalricnauccildea[2r4m].agnetic resonance (NMR; see Figures S1–S13, Supplementary Material) Their lipopAhilllicitthyewcaosmevpalleuxaetsedwbyerRe P-cHhaPrLaCctemriezaesdurewmiethntsr[e4v3e]r.sIendd-epehda,stehe hchigrhompaetorfgorramphainccreetelinqtuioidn wcharsomduaetotgorpaparhtyitio(RniPn-gHbPeLtCw)eecnouCp1l8edchwainitshoefltehcetrsotsaptiroanyarioynpizhaatsieon(a-mmaosdsesl poefctthreomceeltlrmy e(mESbIr-aMneS)) aanndd mthueltainquuceloeuasr neulucelenatr (ma amgnoedteicl roefsothneanwceat(eNrMinRs;idseeeaFnigduoreustsSi1d–eS1c3e,llSs)u.pTphleemleongtaarrityhMmaotefritahle). The half-maximal inhibitory concentrations, IC50, were determined for 2 and 3, along with the clinically-employed reference complexes cisplatin and oxaliplatin, as well as asplatin 1, free
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