title: Multidrug resistance reversal and apoptosis induction in human colon cancer cells by some flavonoids present in citrus plants.
abstract: Multidrug resistance (MDR) of cancer cells constitutes one of the main reasons for chemotherapy failure. The search for nontoxic modulators that reduce MDR is a task of great importance. An ability to enhance apoptosis of resistant cells would also be beneficial. In the present study, the MDR reversal and apoptosis-inducing potency of three flavonoids produced by Citrus plants, namely, naringenin (1a), aromadendrin (2), and tangeretin (3), and the methylated naringenin derivatives (1b, 1c), have been studied in sensitive (LoVo) and multidrug-resistant (LoVo/Dx) human colon adenocarcinoma cells. Cytotoxicity of methoxylated flavonoids was higher as compared to hydroxylated analogues. Only 3 turned out to inhibit P-glycoprotein, as demonstrated by a rhodamine 123 accumulation assay. It also increased doxorubicin accumulation in LoVo/Dx cells and enabled doxorubicin to enter cellular nuclei. In addition, 3 was found to be an effective MDR modulator in resistant cells by sensitizing them to doxorubicin. Tangeretin-induced caspase-3 activation and elevated surface phosphatidylserine exposure demonstrated its apoptosis-inducing activity in LoVo/Dx cells, while the other flavonoids evaluated were not active. Additionally, 3 was more toxic to resistant rather than to sensitive cancer cells. Its apoptosis-inducing activity was also higher in LoVo/Dx than in LoVo cells. It was concluded that the activity of 3 against multidrug-resistant cancer cells may be enhanced by its apoptosis-inducing activity.
authors.affiliation: Department of Biophysics, Wrocław Medical University , ul. Chałubińskiego 10, 50-368 Wrocław, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Wesołowska
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wiśniewski
authors.forename: Kamila
authors.initials: K
authors.lastname: Sroda-Pomianek
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bielawska-Pohl
authors.forename: Maria
authors.initials: M
authors.lastname: Paprocka
authors.forename: Danuta
authors.initials: D
authors.lastname: Duś
authors.forename: Noélia
authors.initials: N
authors.lastname: Duarte
authors.forename: Maria-José U
authors.initials: MJ
authors.lastname: Ferreira
authors.forename: Krystyna
authors.initials: K
authors.lastname: Michalak
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects; D000465:Algorithms; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002957:Citrus / Q000737:chemistry*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D044950:Flavanones / Q000737:chemistry / Q000627:therapeutic use; D047309:Flavones / Q000737:chemistry / Q000627:therapeutic use; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure; D020112:Rhodamine 123 / Q000032:analysis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044950:Flavanones; D047309:Flavones; D005419:Flavonoids; D020112:Rhodamine 123; C080220:aromadedrin; D053148:Caspase 3; C005273:naringenin; C059006:tangeretin