| Reference | [1]. Pharmaceuticals (Basel). 2020 Oct 21;13(10):327. doi: 10.3390/ph13100327.<br />
Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies.<br />
Afonso de Lima C(1), de Souza Bueno IL(1), Nunes Siqueira Vasconcelos S(2)(3)(4), Sciani JM(5), Ruiz ALTG(6), Foglio MA(6), Carvalho JE(6), Barbarini Longato G(1).<br />
Author information: (1)Research Laboratory in Molecular Pharmacology and Bioactive Compounds, São Francisco University, Bragança Paulista, São Paulo 12916-900, Brazil. (2)Center for Medicinal Chemistry (CQMED), University of Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil. (3)Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas, São Paulo 13083-875, Brazil. (4)Structural Genomics Consortium, Department of Genetics and Evolution, Institute of Biology (IB), University of Campinas (UNICAMP), Campinas, São Paulo 3083-866, Brazil. (5)Laboratory of Multidisciplinary Research, São Francisco University, Bragança Paulista, São Paulo 12916-900, Brazil. (6)LAFTEx Faculty of Pharmaceutical Science, University of Campinas, Campinas, São Paulo 13083-859, Brazil.<br />
Multidrug resistance (MDR) is the main obstacle in anticancer therapy. The use of drug combinations to circumvent tumor resistance is a well-established principle in the clinic. Among the therapeutic targets, glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating MDR, is highlighted. Many pharmacological studies report the ability of calcium channel blockers to reverse tumor resistance to chemotherapy drugs. Isolated for the first time from parsley, the phenylpropanoid apiole is described as a potent calcium channel inhibitor. Taking this into account, herein, the ability of apiole to potentiate the action of well-established chemotherapeutics in the clinic, as well as the compound's relationship with the reversal of the resistance phenomenon by blocking P-gp, is reported. The association of apiole with both chemotherapeutic drugs doxorubicin and vincristine resulted in synergistic effect, in a concentration-dependent manner, as evaluated by the concentration reduction index. Molecular docking analysis demonstrated the affinity between apiole and the active site of P-gp, corroborating the inhibitory effect. Moreover, apiole demonstrated druglikeness, according to ADME analysis. In conclusion, apiole possibly blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents.<br />
DOI: 10.3390/ph13100327 PMCID: PMC7589691 PMID: 33096917<br />
<br />
[2]. BMC Complement Altern Med. 2019 Jul 27;19(1):188. doi: 10.1186/s12906-019-2590-9.<br />
Study of the antitumor mechanisms of apiole derivatives (AP-02) from Petroselinum crispum through induction of G0/G1 phase cell cycle arrest in human COLO 205 cancer cells.<br />
Wu KH(1)(2)(3), Lee WJ(4), Cheng TC(5), Chang HW(6), Chen LC(7)(8)(9), Chen CC(10), Lien HM(11), Lin TN(12), Ho YS(13)(14)(15).<br />
Author information: (1)The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan. (2)Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. (3)Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. (4)Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan. (5)School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, 110, Taiwan, Republic of China. (6)Department of Medical Laboratory, and Cancer Research Center of Taipei Medical University Hospital, Taipei, Taiwan. (7)Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan. (8)Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. (9)TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. (10)School of Management, Feng Chia University, Taichung, Taiwan. (11)Research Institute of Biotechnology, Hungkuang University, No.1018, Sec. 6, Taiwan Blvd., Shalu Dist, Taichung City, 43302, Taiwan. [email protected]. (12)Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. [email protected]. (13)School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, 110, Taiwan, Republic of China. [email protected]. (14)Department of Medical Laboratory, and Cancer Research Center of Taipei Medical University Hospital, Taipei, Taiwan. [email protected]. (15)TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].<br />
BACKGROUND: Apiole was isolated from the leaves of various plants and vegetables and has been demonstrated to inhibit human colon cancer cell (COLO 205 cells) growth through induction of G0/G1 cell cycle arrest and apoptotic cell death. This study further explored the antitumor effects of apiole derivatives AP-02, 04, and 05 in COLO 205 cancer cells. METHODS: Human breast (MDA-MB-231, ZR75), lung (A549, PE089), colon (COLO 205, HT 29), and hepatocellular (Hep G2, Hep 3B) cancer cells were treated with apiole and its derivatives in a dose-dependent manner. Flow cytometry analysis was subsequently performed to determine the mechanism of AP-02-induced G0/G1 cell cycle arrest. The in vivo antitumor effect of AP-02 (1 and 5 mg/kg, administered twice per week) was examined by treating athymic nude mice bearing COLO 205 tumor xenografts. The molecular mechanisms of AP-02-induced antitumor effects were determined using western blot analysis. RESULTS: AP-02 was the most effective compound, especially for inhibition of COLO 205 colon cancer cell growth. The cytotoxicity of AP-02 in normal colon epithelial (FHC) cells was significantly lower than that in other normal cells derived from the breast, lung or liver. Flow cytometry analysis indicated that AP-02-induced G0/G1 cell cycle arrest in COLO 205 cells but not in HT 29 cells (< 5 μM for 24 h, **p < 0.01). Tumor growth volume was also significantly inhibited in AP-02 (> 1 mg/kg)-treated athymic nude mice bearing COLO 205 tumor xenografts compared to control mice (*p < 0.05). Furthermore, G0/G1 phase regulatory proteins (p53 and p21/Cip1) and an invasion suppressor protein (E-cadherin) were significantly upregulated, while cyclin D1 was significantly downregulated, in AP-02-treated tumor tissues compared to the control group (> 1 mg/kg, *p < 0.05). CONCLUSIONS: Our results provide in vitro and in vivo molecular evidence of AP-02-induced anti-proliferative effects on colon cancer, indicating that this compound might have potential clinical applications.<br />
DOI: 10.1186/s12906-019-2590-9 PMCID: PMC6660667 PMID: 31351461 [Indexed for MEDLINE]<br />
<br />
[3]. J Cancer Res Ther. 2012 Oct-Dec;8(4):532-6. doi: 10.4103/0973-1482.106529.<br />
The in vivo antitumor effects on human COLO 205 cancer cells of the 4,7-dimethoxy-5-(2-propen-1-yl)-1,3-benzodioxole (apiole) derivative of 5-substituted 4,7-dimethoxy-5-methyl-l,3-benzodioxole (SY-1) isolated from the fruiting body of Antrodia camphorate.<br />
Wei PL(1), Tu SH, Lien HM, Chen LC, Chen CS, Wu CH, Huang CS, Chang HW, Chang CH, Tseng H, Ho YS.<br />
Author information: (1)Department of Surgery, School of Medicine, Taipei Medical University, Taipei, Taiwan.<br />
CONTEXT: The compound 4,7-dimethoxy-5-(2-propen-1-yl)-1,3-benzodioxole (apiole) has been isolated from several different plant species, including Petroselinum sativum. Our recent study found that apiole is a chemical derivative of 4,7-dimethoxy-5-methyl-l,3-benzodioxole (SY-1), which has been isolated from dried Antrodia camphorata (AC ) fruiting bodies, a traditional Chinese medicine with antitumor properties. AIMS: Our previous in vitro study demonstrated that apiole inhibits the growth of human colon (COLO 205) cancer cells through the arrest of the cell cycle in G0/G1 phase. The in vivo antitumor effects of apiole were evaluated in this study. SETTING AND DESIGN: Apiole was administered to mice at 1-30 mg/kg body weight through intraperitoneal (I.P.) injection three times per week (defined as a dosage of 1×-30×). MATERIALS AND METHODS: The in vivo antitumor effects of apiole were evaluated in mice with xenografts of COLO 205 cells. STATISTICAL ANALYSIS: All of the data are reported as the means ± S.E. Comparisons were performed with a one-way analysis of variance (ANOVA) followed by a Fisher's least significant difference test. Significance was defined as P < 0.05. RESULTS: Apiole (> 1×) markedly decreased the growth of COLO 205 human colon cancer cell tumor xenografts in an athymic nude mouse model system through the up-regulation of cell cycle regulators, such as p53, p21/Cip1, and p27/Kip1. The apiole-induced increase in G0/G1 phase cell cycle regulators was also associated with a significant decrease in the expression of cyclins D1 and D3. Surprisingly, statistically significantly higher tumor volumes were observed in mice that received 5× apiole compared with 30× apiole-treated mice (P < 0.05). No gross signs of toxicity were observed (e.g., body weight changes, general appearance, or individual organ effects) in any group. CONCLUSIONS: Our results show, for the first time, the promising antitumor effects of apiole against colon tumors in an in vivo xenograft model.<br />
DOI: 10.4103/0973-1482.106529 PMID: 23361270 [Indexed for MEDLINE]<br />
<br />
[4]. Nature. 1967 Sep 30;215(5109):1494-5. doi: 10.1038/2151494b0.<br />
Psychotrophic phenylisopropylamines derived from apiole and dillapiole.<br />
Shulgin AT, Sargent T.<br />
DOI: 10.1038/2151494b0 PMID: 4861200 [Indexed for MEDLINE]<br />
<br />
[5]. Atti Accad Fisiocrit Siena Med Fis. 1956;3:195-200.<br />
[Quantitative determination of apiole].<br />
[Article in Italian]<br />
BARNI M.<br />
PMID: 13445607 [Indexed for MEDLINE]
|
