RESUMO
Novel demethylcantharidin-platinum (DMC-Pt) complexes have been found to have superior in vitro anticancer activity against a number of human colon cancer cell lines when compared with oxaliplatin. One complex where the DMC-Pt moiety was integrated with trans-R,R-diamino-cyclohexane (DACH), exhibited the most pronounced cytotoxicity. To ascertain the mechanistic contribution of the DMC component, microarray analysis was conducted to compare the effect of the novel (R,R-DACH)-Pt-(DMC) complex and oxaliplatin, on the gene expression of human colorectal cancer (HCT116) cells. The Affymetrix HG-U133A oligonucleotide microarray was used, and the data allowed for the discrimination of genes that were specifically affected by the DMC ligand. One hundred and forty-one genes were found to be up-regulated. Of these, 48 can be classified according to different cellular responses including DNA repair, DNA synthesis, cell adhesion, cell cycle regulation, mitotic spindle checkpoint and apoptosis/antiapoptosis. The DMC ligand is likely to have caused damage to DNA bases and/or strands, and nucleotide mismatch, as highlighted by the recruitment of the repairing genes from the BER, HR and MMR. Antiapoptotic genes such as survivin, BRCA1 and ITGB3BP were up-regulated, and it is proposed that the inherent defense mechanism of the cell may have been triggered, creating potential resistance to apoptosis. This study is the first to demonstrate the impact of the DMC ligand on the gene expression profile of HCT116 colon cancer cells and further substantiates its inclusion in the design of novel platinum-based anticancer complexes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/genética , Expressão Gênica/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Cantaridina/administração & dosagem , Cantaridina/análogos & derivados , Linhagem Celular Tumoral , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Compostos de Platina/administração & dosagemRESUMO
Oxaliplatin is a third generation platinum (Pt) drug with a diaminocyclohexane (DACH) entity, which has recently obtained worldwide approval for the clinical treatment of colon cancer, and apparently operates by a different mechanism of action to the classical cisplatin or carboplatin. Introducing a novel dual mechanism of action is one approach in designing a new platinum-based anticancer agent, whereby an appropriate ligand, such as demethylcantharidin (DMC), is released from the parent compound to exert a cytotoxic effect, in addition to that of the DNA-alkylating function of the platinum moiety. To investigate the likelihood of a novel dual mechanism of anticancer action, demethylcantharidin-integrated Pt complexes: Pt(R,R-DACH)(DMC) with the same Pt-DACH moiety as oxaliplatin, and Pt(NH(3))(2)(DMC) akin to carboplatin; were studied for their ability to induce DNA damage in HCT116 colorectal cancer cells by an alkaline comet assay. The results showed that the DMC ligand released from the novel complexes caused additional DNA lesions when compared with oxaliplatin and carboplatin. The comet assay also revealed that the DNA-damaging behavior of cisplatin is characteristically different; and this study is the first to demonstrate the ability of DMC to induce DNA lesions, thus providing sufficient evidence to explain the superior antiproliferative effect of the novel DMC-integrated complexes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cantaridina/análogos & derivados , Neoplasias Colorretais/genética , Dano ao DNA/genética , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Platina/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Cantaridina/administração & dosagem , Cantaridina/química , Linhagem Celular Tumoral , Humanos , Platina/químicaRESUMO
A series of platinum complexes derived from integrating demethylcantharidin (DMC) with different isomers of 1,2-diaminocyclohexane (DACH) has been synthesized and found to exhibit superior in vitro anticancer activity against colorectal and human hepatocellular cancer cell lines when compared with oxaliplatin, cisplatin, and carboplatin. Flow cytometric analysis revealed that the trans-DACH-Pt-DMC analogues showed similar behavior to oxaliplatin on affecting the cell cycle of the HCT116 colorectal cancer cell line, but distinct from that of cisplatin or carboplatin. The DACH component apparently dictates the trans-DACH-Pt-DMC complexes to behave mechanistically similar to oxaliplatin, whereas the DMC ligand appears to enhance the compounds' overall anticancer activity, probably by accelerating the cell cycle from G1 to S-phase with subsequent onset of G2/M arrest and accompanying apoptosis.
Assuntos
Antineoplásicos/farmacologia , Cantaridina/análogos & derivados , Cicloexilaminas/química , Platina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Cantaridina/química , Cantaridina/metabolismo , Carboplatina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Cisplatino/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Cicloexilaminas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Citometria de Fluxo , Humanos , Isomerismo , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Platina/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Novel TCM-platinum compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)] 1-5, derived from integrating demethylcantharidin, a modified component from a traditional Chinese medicine (TCM) with a platinum moiety, possess anticancer and protein phosphatase 2A inhibition properties. The compounds are able to circumvent cisplatin resistance by apparently targeting the DNA repair mechanism. Novel isosteric analogues [Pt(C(9)H(10)O(4))(NH(2)R)(2)] A and B, devoid of PP2A-inhibitory activity, were found to suffer from an enhanced DNA repair and were cross-resistant to cisplatin. The results advocate a well-defined structure-activity requirement associating the PP2A-inhibiting demethylcantharidin with the circumvention of cisplatin cross-resistance demonstrated by TCM-Pt compounds 1-5.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Cantaridina/análogos & derivados , Cisplatino/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organoplatínicos/síntese química , Fosfoproteínas Fosfatases/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Cantaridina/farmacologia , Cisplatino/farmacologia , Reagentes de Ligações Cruzadas/síntese química , Reparo do DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Medicina Tradicional Chinesa , Compostos Organoplatínicos/farmacologia , Proteína Fosfatase 2 , Relação Estrutura-Atividade , Fatores de Tempo , Células Tumorais CultivadasRESUMO
Dimers of vancomycin (Van), linked by a rigid metal complex, [Pt(en)(H(2)O)(2)](2+), exhibit potent activities (MIC approximately 0.8 mug/mL, approximately 720 times more potent than that of Van itself) against vancomycin-resistant enterococci (VRE). The result suggests that combining metal complexation and receptor/ligand interaction offers a useful method to construct multivalent inhibitors.
Assuntos
Antibacterianos/síntese química , Enterococcus/efeitos dos fármacos , Compostos Organoplatínicos/síntese química , Vancomicina/análogos & derivados , Antibacterianos/farmacologia , Dimerização , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Compostos Organoplatínicos/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Termodinâmica , Vancomicina/síntese química , Vancomicina/farmacologia , Resistência a VancomicinaRESUMO
A vancomycin (Van) derivative self-assembles in a phosphate buffer as a divalent Van and on cell surfaces as a multivalent Van, which offers potent activity against VRE.
Assuntos
Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Resistência a Vancomicina , Vancomicina/análogos & derivados , Vancomicina/farmacologia , Antibacterianos/química , Ligação Competitiva , Dimerização , Testes de Sensibilidade Microbiana , Vancomicina/químicaRESUMO
After conjugation to vancomycin (Van), chemically stable and highly magnetic anisotropic FePt magnetic nanoparticles (approximately 4 nm) become water-soluble and capture E. coli at 15 cfu mL(-1).
RESUMO
Antibiotic hydrogels based on a vancomycin (Van) derivative, formed by self-assembling Van-pyrene (1) in water, using the pi-pi interaction of pyrene moieties and hydrogen bonding of Vans, promise a new way to make novel biomaterials.