Cytotoxic activity and cell cycle analysis of quinoline alkaloids isolated from Haplophyllum canaliculatum Boiss.
Bioassay-guided fractionation of Haplophyllum canaliculatum Boiss. (Rutaceae) extract resulted in isolation of five quinoline alkaloids: 7-isopentenyloxy-gamma-fagarine, atanine, skimmianine, flindersine and perfamine. This is the first isolation of these compounds from this endemic species. The antitumor activity of these five isolates was evaluated against RAJI, Jurkat, KG-1a, HEP-2, MCF-7, HL-60 and HL-60/MX1 tumor cell lines. The highest cytotoxic effect was observed on acute lymphoblastic leukemia cell lines. 7-Isopentenyloxy-gamma-fagarine, atanine, skimmianine and flindersine exhibited very high cytotoxicity against the RAJI cell line with IC(50) values of 1.5, 14.5, 15.6 and 14.9 microg/mL, respectively and 7-isopentenyloxy-gamma-fagarine, atanine and skimmianine exhibited very high cytotoxicity against the Jurkat cell line with IC(50) values of 3.6, 9.3 and 11.5 microg/mL, respectively. 7-Isopentenyloxy-gamma-fagarine was also highly cytotoxic against the MCF-7 cell line (IC(50) = 15.5 microg/mL), while atanine, skimmianine, flindersine and perfamine showed moderate to low activity against these cells. All alkaloids had moderate to low cytotoxicity against KG-1a and HEP-2. Investigation of the toxic potential of the alkaloids on HL-60 and HL-60/MX1 showed a significantly higher effect against HL-60/MX1, a multidrug-resistant cell line, compared with the control etoposide (p < 0.05). In all cytotoxicity experiments, peripheral blood mononuclear cells (PBMC) were used as a control for normal hematopoietic cells. Flow cytometry analysis of the compounds resulted in the arrest of cell cycle progression at the sub-G1 phase of the RAJI and Jurkat cell lines in a dose-dependent manner. According to computational analyses, the similar cytotoxic trend in the cell lines could be indicative of the fact that these compounds may act through parallel mechanisms.
Varamini
Pegah
P
Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran.
Javidnia
Katayoun
K
Soltani
Mohammad
M
Mehdipour
Ahmad Reza
AR
Ghaderi
Abbas
A
D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D009369:Neoplasms / Q000188:drug therapy*; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D027821:Rutaceae / Q000737:chemistry*
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D011804:Quinolines; D005047:Etoposide