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| 11. |
Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase–Akt/PKB survival pathway |
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Anti-Cancer Drugs,
Volume 14,
Issue 2,
2003,
Page 167-173
Gerald Ruiter,
Shuraila Zerp,
Harry Bartelink,
Wim van Blitterswijk,
Marcel Verheij,
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摘要:
Synthetic alkyl-lysophospholipids (ALPs) represent a new class of anti-tumor agents that target cell membranes and induce apoptosis. However, the exact mechanisms by which ALPs exert these effects remain unclear. Here, we investigated in the epithelial carcinoma cell lines A431 and HeLa the effect of three clinically relevant ALPs [Et-18-OCH3(Edelfosine), HePC (Miltefosine) and D-21266 (Perifosine)] on the phosphatidylinositol 3-kinase (PI3K)–Akt/PKB survival pathway. We found that growth factor-induced Akt/PKB activation in these cells is dependent on PI3K and that all three ALPs inhibited this pathway in a dose-dependent manner. We further showed that inhibition of the PI3K–Akt/PKB pathway by wortmannin or ALPs is associated with activation of the pro-apoptotic SAPK/JNK pathway. Inhibition of the PI3K–Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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| 12. |
Differential effects of the optical isomers of KR30031 on cardiotoxicity and on multidrug resistance reversal activity |
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Anti-Cancer Drugs,
Volume 14,
Issue 2,
2003,
Page 175-181
Byung Lee,
Chong Lee,
Myung-Ja Kwon,
Kyu Yi,
Sung-eun Yoo,
Sang-Un Choi,
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PDF (244KB)
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摘要:
The present study was performed to compare the cardiovascular adverse effects of verapamil, KR30031 and their optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). TheR-isomer of KR30031 (R-KR30031) was equipotent with theS-isomer of KR30031 (S-KR30031) and 25-fold less potent than theR-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 μM, respectively). The effect ofR-KR30031 in decreasing left ventricular pressure of heart isolated from rat was 2- and 267-fold smaller than those ofS-KR30031 andR-verapamil, respectively (EC50: 23.9, 9.4 and 0.089 mM, respectively). The hypotensive effect ofR-KR30031 in rat was about 2- and 23-fold smaller than those ofS-KR30031 andR-verapamil, respectively (ED20: 1.15, 0.60 and 0.05 mg/kg, respectively). On the other hand,R-KR30031 elicited potency similar to those ofS-KR30031 andR-verapamil in enhancing the paclitaxel-induced cytotoxicity to HCT15/CL02 and MES-SA/DX5 cells that reveal high levels of P-glycoprotein expression (IC50: 3.11, 3.04 and 2.58 μM, respectively). In addition, the intrinsic cytotoxicity ofR-KR30031 in HCT15/CL02 and MES-SA/DX5 cells was observed only at the very high concentration of 100 μM. All these results suggest thatR- and racemic KR30031 are active modulators of MDR with potentially minimal cardiovascular adverse activity.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
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