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Oral cavity cancer is the seventh most common type of cancer among Brazilians. For the biennium 2018-2019 is estimated 14,700 new cases1. Oral squamous cell carcinoma (OSCC) is the most common head and neck tumor, accounting for approximately 90% of oral malignancies. Currently, chemotherapeutics of natural origin has a prominent role in the treatment of cancer and works with Piper spp. have shown that these plants produce various cytotoxic and antitumor substances2. Thus, the objective of this work is to evaluate the cytotoxic effect of Piper cernuum Vell fractions using three human oral squamous cell carcinoma lines (OSCC4, OSCC9 and OSCC25), fibroblasts and perform chemical analyzes of the active fractions. The crude extract of P. cernuum leaves (EBFPC) was produced for static maceration with methanol. The extract was solubilized in MeOH:H2O 1:1 (v/v) and chromatographic partitions were prepared by polarity gradient (hexane, CH2Cl2, AcOEt, BuOH). The dichloromethane partition was subjected to vacuum liquid chromatography method using a solvent gradient system (Hexane, CH2Cl2, AcOEt, MeOH e H2O). Extract, partitions and fractions were tested by clonogenic and cell viability (MTT assay3), using carboplatin as positive control. OSCC cell lines (SCC4, SCC9, SCC25) and primary human fibroblasts were used for all assays. The crude extract significantly reduced the cell density of the SCC9 line at all concentrations tested (1.5 and 25μg/mL) presenting IC50 of 106.3±0.06 μg/mL, while carboplatin (reference drug) presented IC50 of 225.3±0.09 μg/mL. The dichloromethane partition (IC50≅47µg/mL) was more active although all partitions showed cytotoxicity: it caused a permeabilization of 6.5 times more cells than the standard that is partition-induced reduction of cell number; was not hemolytic and not acutely toxic in mice. Seventeen fractions were obtained from the dichloromethane partition, these fractions seven (3, 5, 6, 9, 10, 12, 14) were selected and analyzed for its cytotoxicity and fractions 9 (IC50=40.25 µg/mL) and 12 (IC50=45.08 µg/mL) were the most active, with values smaller than the standard (IC50=322.30 µg/mL) and fractions 9, 10, 14 the most selective with 2.67, 3.59 and 31.78 of selectivity, respectively. Ten fractions obtained from fractions 9 and 14 were assayed on OSCC9 lineage tumor cells and fibroblasts, where fractions 09-07 (IC50 = 74.71 µg/mL) and 14-05 (IC50 = 162.6 µg/mL) were the most selective, presenting a selectivity of 2.03 and 2.53, respectively. The active fractions were analyzed by GC-MS and dichloromethane fraction allowed the identification of five dibenzylbutyrolactone lignans: 8’,9’-dihydro-3,4,3’,4’-dimethylenodioxylignan, 3,4,3’,4’-dimethylenodioxylignano-9,9’-lactol, 3,4-methylenodioxy-3’,4’-dimethoxylignano-9,9’-lactol, 3,4,3’,4’-dimethylenodioxylignano-9,9’-lactone and 3,4-methylenodioxy-3’,4’-dimethoxylignano-9,9’-lactone; and three sesquiterpenes: octahydro-2,2,5a,9-tetramethyl-2H-3,9a-methano-1-benzoxepin, methyl 3-(3,4-dimethoxyphenyl) propanoate and neophytadiene. After analysis it can be concluded that the extracts, partitions and fractions of P. cernuum were active against the cell lines of SCC9, showed a significant inhibitory effect on the viability of OSCC9.The determination of major substances present in the most active and selective partitions and cell death pathway are in course.
Agradecimentos: CNPq, FAPERJ e CAPES.
1. INCA. Estimativa. 2017, 128.
2. Gutierrez, R. M. P. et al. Mini-Reviews in Medicinal Chemistry, 2013, 13, 163-193.
3. Mosmann, T. J. of Immunology Met., 1983, 65, 55-63
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