In vitro and in vivo antitumor effects of (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone.
OBJECTIVE
(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a phenstatin analog compound. PHT is a known tubulin inhibitor that has potent cytotoxic activity. In the present study, PHT was synthesized and its antitumor activity was determined using in vitro and in vivo experimental models.


METHODS
The in vitro cytotoxic activity of the PHT was determined by the MTT assay. The antimitotic and hemolytic effects were determined based on the inhibition of sea urchin embryo development and lysis of mouse erythrocytes, respectively. In vivo antitumor activity was assessed in mice inoculated with sarcoma 180 cells.


RESULTS
In vitro, PHT displayed cytotoxicity in tumor cell lines, showing IC(50) values in the nanomolar range. In addition, it inhibited sea urchin embryo development during all phases examined, first and third cleavage and blastula stage. However, PHT did not induce hemolysis using mouse erythrocytes, suggesting that the cytotoxicity of PHT does not involve membrane damage. The in vivo study demonstrated tumor inhibition rates of 30.9 and 48.2% for PHT at doses of 20 and 40 mg/kg, respectively. In addition, PHT was also able to increase the response elicited by 5-fluorouracil (5-FU) from 33.3 to 55.7%. The histopathological analysis of liver, kidney, and spleen showed that they were just moderately affected by PHT treatment. Neither enzymatic activity of transaminases nor urea levels were significantly affected. Hematological analysis showed leukopenia after 5-FU treatment, but this effect was prevented when 5-FU was combined with PHT.


CONCLUSIONS
In conclusion, PHT exhibited in vitro and in vivo antitumor effects without substantial toxicity.
Magalhães
Hemerson Iury F
HI
Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.
Bezerra
Daniel P
DP
Cavalcanti
Bruno C
BC
Wilke
Diego V
DV
Rotta
Rodrigo
R
de Lima
Dênis P
DP
Beatriz
Adilson
A
Alves
Ana Paula N N
AP
Bitencourt
Flávio da S
Fda S
de Figueiredo
Ingrid S T
IS
Alencar
Nylane M N
NM
Costa-Lotufo
Letícia V
LV
Moraes
Manoel Odorico
MO
Pessoa
Claudia
C
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000633:toxicity; D050256:Antimitotic Agents; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001577:Benzophenones / Q000494:pharmacology* / Q000633:toxicity; D049108:Cell Enlargement / Q000187:drug effects*; D045744:Cell Line, Tumor; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology / Q000633:toxicity; D018922:HL-60 Cells; D006461:Hemolysis; D006801:Humans; D008297:Male; D051379:Mice; D012617:Sea Urchins / Q000196:embryology; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000633:toxicity
C560639:(4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone; D000964:Antimetabolites, Antineoplastic; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D001577:Benzophenones; D050257:Tubulin Modulators; D005472:Fluorouracil