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Effect of stealthy liposomal topotecan plus amlodipine on the multidrug‐resistant leukaemia cells in vitro and xenograft in mice
Author(s) -
Li X.,
Lu W. L.,
Liang G. W.,
Ruan G. R.,
Hong H. Y.,
Long C.,
Zhang Y. T.,
Liu Y.,
Wang J. C.,
Zhang X.,
Zhang Q.
Publication year - 2006
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2006.01643.x
Subject(s) - topotecan , pharmacology , chemistry , multiple drug resistance , cytotoxicity , apoptosis , p glycoprotein , k562 cells , caspase , in vitro , cancer research , medicine , chemotherapy , biochemistry , programmed cell death , antibiotics
Background Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy as the over‐expressed MDR protein acts as an efflux pump, which leads to a reduction in the uptake of the anticancer agent by tumour cells. We combined topotecan and amlodipine together into the stealthy liposomes, in which amlodipine was applied as a MDR reversing agent to overcome the resistance. Materials and methods Cytotoxicity, apoptosis and the signalling pathway assays were performed on human chronic myelogenous leukaemia K562, promyelocytic leukaemia HL‐60 and MDR HL‐60 cells, respectively. Pharmacokinetics and antitumour activity studies were performed on normal Kunming mice and female BALB/c nude mice with MDR HL‐60 xenografts, respectively. Results Topotecan alone was effective in inhibiting the growth of non‐resistant leukaemia cells, K562 and HL‐60 cells but not the growth of MDR HL‐60 cells. The resistance of topotecan in MDR HL‐60 cells was potently reversed by the addition of amlodipine. Moreover, amlodipine enhanced the apoptosis‐inducing effect of topotecan synergistically. Apoptosis was through activating caspases in a cascade: first, the initiator caspase 8 and then effectors caspase 3/7 (total activity of caspases 3 and 7) were activated. Being encapsulated into the stealthy liposmes with an acidic internal medium, topotecan existed dominantly in an active lactone species, which was reversibly changed from an inactive carboxylate form via a pH‐dependent reaction. After administration of stealthy liposomes to mice, the blood exposure of the lactone form was evidently increased and extended. The antitumour effects in the MDR HL‐60 xenografted tumour were stealthy liposomal topotecan (SLT) plus amlodipine > SLT > un‐encapsulated topotecan > blank control. Conclusions The enhanced antitumour activity in the MDR HL‐60 cells by the SLT plus amlodipine could be owing to multiple reasons: (a) synergistic apoptosis inducing effect, (b) reversing MDR by amlodipine and (c) increasing the availability of active lactone of topotecan by the stealthy liposomes. The apoptosis induced by amlodipine is through caspase 8 and then the 3/7 signalling pathway.