A novel stealth liposomal topotecan with amlodipine: Apoptotic effect is associated with deletion of intracellular Ca2+ by amlodipine thus leading to an enhanced antitumor activity in leukemia

A Continued Study on the Stealth Liposomal Topotecan Plus Amlodipine: In Vitro and In Vivo Characterization in Non-Resistant Solid Tumors

“…A large number of anti-tumor agents including topotecan are becoming insensitive or even ineffective to tumor cells owing to multi-drug resistance (MDR), [1][2][3] which refers to a cross-resistance of tumor cells to not only a single type but also a series of structurally different anti-tumor drugs and is often found in a variety of human malignancies that have relapsed after initial treatment. 2,4,5) Since MDR has become one of the major causes leading to the failure of cancer chemotherapy, many studies are focused on the strategies to overcome MDR.…”

“…: +86-10-8280-2683; Fax: +86-10-8280-2683; E-mail: luwl@bjmu.edu.cn viously established a type of anti-resistant stealth liposomal topotecan plus amlodipine through which we successfully incorporated topotecan with amlodipine together into stealth liposomes using the ammonium sulphate gradient method. 1) Topotecan was used as a cytotoxic agent and amlodipine was adopted as a "modulator," aiming at overcoming MDR caused by the overexpression of Pglycoprotein (P-gp or ABCB1) in human resistant leukemia cells (MDR HL-60 and MDR K562). Results demonstrated that amlodipine was an effective modulator capable of reversing the MDR in resistant leukemia cells in vitro and in vivo.…”

“…The LOQ was 0.03 µg/ml and linearity ranged from 0.5-30.0 µ g/ml (R 2 = 0.9999). Preparation of Liposomes --Six kinds of liposomes were prepared using the ammonium sulfate gradient method according to our previous report, 1,16) Topotecan and/or amlodipine concentrations in the liposomes were less than 1.5 mg/ml to ensure high drug encapsulation efficiencies. Typically, the encapsulation efficiencies for topotecan and amlodipine were ≥ 95% and 90%, respectively.…”

“…The mice were monitored daily for their tumor volumes (V, calculated by the following formula: V = length × width × 0.52, mm 3 ) and divided into seven groups (5 or 6 each group) on the 6th day. 1) In addition, on the 6th, 8th and 10th day after tumor inoculation, physiological saline, free topotecan (5 mg/kg), free amlodipine (3 mg/kg), free topotecan (5 mg/kg) plus free amlodipine (3 mg/kg), bare liposomal topotecan (5 mg/kg), stealth liposomal topotecan (5 mg/kg) and stealth liposomal topotecan (5 mg/kg) plus amlodipine (3 mg/kg) were given to mice via tail vein, respectively. The change ratio for tumor volume, as an indicator of anti-tumor activities, was calculated using the following formula: the change ratio for tumor volume (%) on the nth day = 100 × (V nth − V 6th )/V 6th , where V nth represented the tumor volume on the nth day and V 6th indicated the tumor volume on the 6th day.…”

The use of functional epirubicin liposomes to induce programmed death in refractory breast cancer

“…The activation of Bax, the inhibition of Mcl-1, the release of cytochrome C (Figure S2D), and the subsequent activation of caspases 9 and 3 ( Figure S2E and F) would result in a cascade of apoptotic reactions. 37 Furthermore, recent studies revealed that the ROS mediate mitochondrial permeability transition, which results in increased expression of apoptotic proteins, such as Bax and caspase 9. 38 The ROS thus generated might be involved in damaging the mitochondrial membrane, and might contribute partially to the release of cytochrome C, the upregulation of Bax, and the activation of caspase 9, thereby inducing cell apoptosis via the mitochondrial pathway.…”