title: 6-Acetonyldihydrochelerythrine Is a Potent Inducer of Apoptosis in HCT116 and SW620 Colon Cancer Cells.
abstract: 6-Acetonyldihydrochelerythrine (1), a benzophenanthridine alkaloid, isolated from the methanol extract of Zanthoxylum capense, displayed potent cytotoxic activity in human HCT116 and SW620 colon carcinoma cells, to a higher extent than 5-fluorouracil (5-FU), the cornerstone chemotherapeutic agent in colon cancer. Cytotoxicity of 1 was evaluated by MTS, lactate dehydrogenase (LDH), and Guava ViaCount assays. Interestingly, 1 significantly induced cytotoxicity in both cell lines, leading to a significant increase in LDH release, as compared to 5-FU. Further, Guava ViaCount flow cytometry assays demonstrated that 1 significantly increased cell death, as shown by the presence of a significantly higher population of apoptotic cells in both cell lines, as compared to cells exposed to 5-FU. Furthermore, evaluation of nuclear morphology by Hoechst staining of 1-treated HCT116 and SW620 cells confirmed flow cytometry results, demonstrating a marked induction of apoptotic cell death by 1, again to a further extent than that elicited by 5-FU. In addition, immunoblot analysis to ascertain the molecular events triggered by 1 exposure was performed. The results show that 1 exposure reduced the steady-state expression and activation of the pro-survival proteins ERK5 and Akt and increased the steady-state expression of p53 in both HCT116 and SW620 cells. Changes in ERK5 or Akt activation can be ascertained by evaluating the ratio of p-ERK5/ERK5 or p-Akt/Akt. In addition, exposure to 1 reduced expression of XIAP, Bcl-XL, and Bcl-2, while increasing the cleavage of poly(ADP-ribose) polymerase in both cell lines. Collectively, the data indicate that 6-acetonyldihydrochelerythrine (1) is a potent inducer of apoptosis in HCT116 and SW620 cell lines, highlighting its potential relevance in colon cancer.
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon , 1649-003 Lisbon, Portugal.
authors: Tayyab A
authors: TA
authors: Mansoor
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon , 1649-003 Lisbon, Portugal.
authors: Pedro M
authors: PM
authors: Borralho
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon , 1649-003 Lisbon, Portugal.
authors: Xuan
authors: X
authors: Luo
authors: Centro de Estudos Moçambicanos e de Etnociências, Faculty of Natural Sciences and Mathematics, Pedagogical University , 21402161 Maputo, Mozambique.
authors: Silva
authors: S
authors: Mulhovo
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon , 1649-003 Lisbon, Portugal.
authors: Cecília M P
authors: CM
authors: Rodrigues
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon , 1649-003 Lisbon, Portugal.
authors: Maria-José U
authors: MJ
authors: Ferreira
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D015394:Molecular Structure; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D032106:Zanthoxylum / Q000737:chemistry*
chemical_list: C473637:6-acetonyldihydrochelerythrine; D000470:Alkaloids; D000970:Antineoplastic Agents; D010616:Phenanthrenes; D011065:Poly(ADP-ribose) Polymerases; D005472:Fluorouracil