title: In vitro and in vivo antitumor effect of 5-FU combined with piplartine and piperine.
abstract: It has been reported that piplartine and piperine, alkaloid/amide compounds from Piper species, show antitumor activities. In the present paper, the effects of the combination of 5-fluorouracil (5-FU) with piplartine or piperine was determined using in vitro and in vivo experimental models. Hematological and biochemical analyses, as well as histopathological and morphological analyses of the tumor and the organs, including liver, spleen and kidney, were performed in order to evaluate the toxicological aspects associated with different treatments. The incubation of tumor cell lines with 5-FU in the presence of piplartine or piperine produced an increase in growth inhibition, as observed by lower IC50 values for 5-FU. These effects were also observed in vivo, where the combination with piplartine but not piperine with 5-FU led to a higher tumor growth inhibition. The results indicated that either piplartine- or 5-FU-treated animals showed a low inhibition rate when they were used individually at low doses of 28.67% and 47.71%, respectively, but when they were combined at the same dose, the inhibition rate increased significantly to 68.04%. The histopathological analysis showed that the livers and the kidneys of treated animals were only slightly and reversibly affected. Neither the enzymatic activity of transaminases nor the urea levels were significantly modified when compared with the control group. Hematological analysis showed leukopenia after 5-FU treatment, which was reversed by the combined use of piplartine and piperine. These findings indicate that piplartine may enhance the therapeutic effectiveness of chemotherapeutic drugs, and moreover, this combination could improve immunocompetence hampered by 5-FU.
authors.affiliation: Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Caixa Postal 3157, 60430-270 Fortaleza, Ceará, Brazil.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bezerra
authors.forename: Fernanda O
authors.initials: FO
authors.lastname: de Castro
authors.forename: Ana Paula N N
authors.initials: AP
authors.lastname: Alves
authors.forename: Cláudia
authors.initials: C
authors.lastname: Pessoa
authors.forename: Manoel Odorico
authors.initials: MO
authors.lastname: de Moraes
authors.forename: Edilberto R
authors.initials: ER
authors.lastname: Silveira
authors.forename: Mary Anne S
authors.initials: MA
authors.lastname: Lima
authors.forename: Francisca Juliana M
authors.initials: FJ
authors.lastname: Elmiro
authors.forename: Nylane M N
authors.initials: NM
authors.lastname: de Alencar
authors.forename: Rodney O
authors.initials: RO
authors.lastname: Mesquita
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lima
authors.forename: Letícia V
authors.initials: LV
authors.lastname: Costa-Lotufo
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000470:Alkaloids / Q000008:administration & dosage; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000097:blood; D052117:Benzodioxoles / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage; D010881:Piperidones / Q000008:administration & dosage; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014508:Urea / Q000097:blood
chemical_list: D000470:Alkaloids; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D052117:Benzodioxoles; D010880:Piperidines; D010881:Piperidones; D053284:Polyunsaturated Alkamides; C498077:piperlongumine; D014508:Urea; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005472:Fluorouracil; C008922:piperine