## 6 Pharmacological Properties of _Apium_ Plants
### Bioactivities of Phytochemicals Identified in Apium spp.
It was shown that 3-\(n\)-butylphthalide (3) markedly reversed the number of apoptotic cells amyloid-\(\beta\)-induced and, in addition, it significantly decreased the hyperphosphorylation of tau protein [172]. Perillyl alcohol (\(p\)-mentha-1,8-dien-7-ol) (4), a limonene-type monoterepenoid consisting of a cyclohexene ring substituted by a hydroxymethyl and a prop-1-en-2-yl group at positions 1 and 4, respectively. It is another constituent of _A. graveolens_ seed-oil and other essential oils such as those obtained from lavendin, peppermint, spearmint, and cherries. It has been proven to interact with several modulators of cell growth and differentiation. The observed activities included the induction of differentiation, cell cycle arrest in the G1 phase, and apoptosis [212,213]. The effectiveness of this monoterepenoid alcohol as an anticancer agent has been tested in a phase II clinical trial for the treatment of patients with metastatic breast cancer refractory to chemotherapy [214]. It showed a modulation in the regulation of the phosphorylation for several cellular factors in human tumor cells, namely, PKB/Akt, 4E-BP1 and eIF4E/eIF4G [212]. Perillic acid (4-isopropylcyclohex-1-encarboxylic acid) (5), one metabolite strictly related to perillyl alcohol, showed also antiproliferative activity on non-small cell lung cancer cells (NSCLC, A549, and H520). As well as perillyl alcohol (4), perillic acid (5) by increasing expression of bax, p21. and caspase-3 activity, exerted a dose-dependent cytotoxicity. Dose-dependent sensitization to cisplatin and radiation in cells exposed to these compounds was also observed. Therefore, their use in combination therapy might have a chemotherapeutic value [213]. The polyacetylene falcarinol ((3\(R\),9_Z_)-heptadeca-1,9-dien-4,6-diyn-3-ol) (6) is another peculiar phytoconstituent of the _Apium_ spp. and more, in general, of several Apiaceae species. It is known to possess an anticancer activity [215,216,217,218]. It has been tested in in vitro experiments against many cancer cell lines, namely, L-1210 (leukemia), MK-1 (human gastric adenocarcinoma), B-16 (mouse melanoma), and L-929 (mouse fibroblast-derived tumor cells). It resulted in being most effective against MK-1 cells, showing an ED\({}_{50}\) value of 0.027 ug/mL [219,220,221]. There are also more widespread phytoconstituents in celery and in other common foods [222] with interesting bioactivities such as is the case of flavonoids and coumarins. Their mechanism of action is generally due to the antioxidant potentialities, such as in the case of coumarins which prevent the formation of free radicals, hence the damaging of cells. This decreases the mutations incidence thus lowering the potential for cells to become cancerous. The flavonoid apigenin (5,7-dihydroxy-2-(4-hydroxyphenyl)-4\(H\)-chromen-4-one) (7) is a widely distributed compound in the plant kingdom. It has also been recognized among the phytoconstituents of _Apium_ species. Apigenin (7) was found to inhibit the growth of prostate tumor in athymic nude mice model by down-modulation of several cyclin proteins, namely D1, D2, E, CDK2, CDK4, CDK6, Cip1/p21, and Kip1/p27, after oral administration. The cell cycle of several cell lines (i.e., pancreatic cancer cell Hep G2 HT-29 and MG63) was blocked in G0/G1 or in G2/M phase, thus inducing apoptosis. A comparison of the spectra for tumor antiproliferation have shown that the flavonoids possess potent antiproliferative activity in the order of luteolin (8), greater than baialein (9) and finally baialin (10) [223,224]. Baicalein (5,6,7-trihydroxy-2-phenyl-4\(H\)-chromen-4-one) (9) proved to inhibit the proliferation of several carcinoma cells (leukemia, hepatoma, breast, and bladder) [225; 226; 227; 228], whereas, baicalin (5,6,7-trihydroxyflavone-7-O-b-p-glucuronide) (10) resulted in being effective against hepatoma and bladder carcinoma cells.