Methyl nomilinate from citrus can modulate cell cycle regulators to induce cytotoxicity in human colon cancer (SW480) cells in vitro.
Limonoids are triterpenoids found in citrus and possess cancer preventive properties in in vitro and in vivo assays. Although several mechanisms for the chemopreventive properties of limonoids have been postulated, the specific mechanisms involved in the anti-cancer effects have not been explored. In the present study, limonoids, including methyl nomilinate, isoobacunoic acid, isolimonexic acid (ILNA), and limonexic acid (LNA), were purified, identified by LC-MS and NMR spectral data and evaluated for their biological effects on SW480 human colon adenocarcinoma cells. Methyl nomilinate was the most potent inhibitor of cell metabolic activity in MTT and EdU incorporation assays. These limonoids did not affect apoptotic markers such as caspase-3 and PARP, but methyl nomilinate treatment resulted in significant induction of G0/G1 cell cycle arrest. Furthermore, methyl nomilinate suppressed CDK4/6 and cyclin D3 and the expression of CDK inhibitors. Taken together, the results suggest inhibition of cell proliferation by methyl nomilinate occurs due to G1 cell cycle arrest, indicating that methyl nomilinate has potential as a chemopreventive agent.
Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University, College Station, TX 77845-2119, USA.
Jinhee
J
Kim
Guddadarangavvanahally K
GK
Jayaprakasha
Amit
A
Vikram
Bhimanagouda S
BS
Patil
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002957:Citrus / Q000737:chemistry*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056743:Cyclin D3 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors; D006801:Humans; D036701:Limonins / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*
D000970:Antineoplastic Agents; C534696:CCND3 protein, human; D056743:Cyclin D3; D004791:Enzyme Inhibitors; D036701:Limonins; D010936:Plant Extracts; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6