Abstract
Inhibitors of calcium-calmodulin-dependent processes, 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-piperazine KN-62 and trifluoperazine (TFP), at non-cytotoxic concentrations (2 and 5 microM, respectively) enhanced etoposide (VP-16) cytotoxicity in Adriamycin-resistant (HL-60/ADR0.05) cells (3- to > 50-fold). In contrast to TFP, the inhibitor KN-62 was able to reverse resistance in HL-60/ADR0.05 cells at VP-16 concentrations that produced equivalent cytotoxicity in sensitive (HL-60/S) cells. Unlike TFP, the cellular accumulation of VP-16 in the presence of KN-62 was enhanced 1.5- to 2-fold in HL-60/S (MDR1 -ve) and HL-60/ADR0.05 (MDR1 +ve) cells. To achieve equivalent cytotoxicity, levels of VP-16 in the resistant cells were > 4-fold lower in the presence of KN-62 compared with treatment with VP-16 alone. The sensitizing effects of both KN-62 and TFP were due to enhancement (2- to 4-fold) of VP-16-induced topoisomerase II (TOPO II)-mediated DNA cleavable complex formation, and depletion of the 170 kDa (alpha) TOPO II isoform. The DNA damage induced by VP-16 in the presence of KN-62 or TFP resulted in the rapid induction of apoptosis and depletion of cells in "S" phase of the cell cycle. Both 5 microM TFP and 2 mic...Continue Reading
References
Jul 1, 1975·The Journal of Cell Biology·A Krishan
Sep 1, 1979·Proceedings of the National Academy of Sciences of the United States of America·H TowbinJ Gordon
Jan 19, 1979·Biochimica Et Biophysica Acta·D T Vistica
Jun 15, 1991·Biochemical Pharmacology·R GanapathiA Anderson
Oct 1, 1990·Biochemical Pharmacology·R GanapathiR Neelon
Jan 1, 1990·Advances in Pharmacology·E GeorgesV Ling
Jan 1, 1989·Annual Review of Biochemistry·J A Endicott, V Ling
Sep 26, 1988·FEBS Letters·M Y HurwitzA R Means
Aug 15, 1970·Nature·U K Laemmli
Jul 1, 1982·Biochemical Pharmacology·B WeissT L Wallace
Mar 1, 1984·Cancer Treatment Reviews·R Osieka
Oct 13, 1995·Biochemical and Biophysical Research Communications·N H ObataH Hidaka
Jan 1, 1993·Cytotechnology·J M Ford, W N Hait
Jan 1, 1994·Cancer Investigation·Y PommierK W Kohn
Jan 1, 1994·Annual Review of Pharmacology and Toxicology·A Y Chen, L F Liu
Jan 1, 1993·Advances in Enzyme Regulation·W T BeckM Chen
Jan 1, 1993·Advances in Cancer Research·K V ChinM M Gottesman
Jan 1, 1996·British Journal of Cancer·K I KawamuraR Ganapathi
Feb 1, 1996·Cancer Genetics and Cytogenetics·R GanapathiJ Ford
Oct 20, 2009·Journal of the American Academy of Dermatology·Khalid A Al JohaniStefano Fedele
Citations
Jul 19, 2000·Archives of Biochemistry and Biophysics·N MukerjeeK K Wang
Jun 16, 2001·Cell Biology International·M SalidoG M Roomans
Feb 1, 2012·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Noriyuki TakaiHisashi Narahara
Jun 18, 2002·Cancer Letters·Noriyuki TakaiIsao Miyakawa
Mar 15, 2001·Neuroscience Letters·K M McGinnisM E Gnegy
Apr 13, 2000·Bioorganic & Medicinal Chemistry Letters·P G BaraldiF di Virgilio
Jul 31, 1998·Leukemia & Lymphoma·S H KaufmannJ E Karp
Jan 27, 2009·Cancer Letters·Noriyuki TakaiHisashi Narahara
Aug 1, 1998·The Journal of Biological Chemistry·K M McGinnisK K Wang
Aug 2, 2001·The Journal of Biological Chemistry·M KruideringE Vreugdenhil
Mar 29, 2001·The Journal of Biological Chemistry·M K JangJ W Lee
Sep 18, 2001·The Journal of Biological Chemistry·Y C SohnS K Lee
Dec 15, 2000·The Journal of Biological Chemistry·M TabataR Ganapathi
Aug 13, 2011·Molecular Cancer Therapeutics·Naoki MineTakumi Kawabe
Jul 8, 1999·The American Journal of Pathology·G PanJ M McDonald
Sep 23, 1998·Biochemical Pharmacology·D R GrabowskiR Ganapathi