Enhanced Cytotoxicity of Рhotoexcited Fullerene C60 and Cisplatin Combination Against D Rugresistant Leukemic Cells

Abstract

Aim: To evaluate the viability of leukemic cells sensitive (L1210S) and resistant (L1210R) to cisplatin, ROS production and free cytosolic Ca2+ concentration under treatment with cisplatin or its combination with photoexcited fullerene C60. Methods: Cell viability was assessed by the MTT reduction assay. Light-emitting diode lamp (2.45 J/сm2) was used for photoexcitation of intracellular accumulated fullerene C60. Free cytosolic calcium concentration ([Ca2+]i) and ROS production in cells were estimated with the use of fluorescent probes Indo-1 and 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA), respectively. Results: It is shown that viability of L1210R cells wasn’t changed under treatment with cisplatin in concentration range 0.1–10 μg/ml. 50% and 30% decrease of L1210S cells were observed after 24 h of incubation with cisplatin at concentrations 5 and 1 μg/ml, respectively. Intensification of extranuclear cytotoxic effects (ROS production and [Ca2+]i increase) after treatment with 1 μg/ml was detected in L1210S, but not in L1210R cells. The most strongly pronounced increase of ROS production and [Ca2+]i in both L1210 cell lines was revealed in dynamics after combined treatment with cisplatin (1 μg/ml) and photoexcited fullerene C60 (10–5 M) and was followed by decreased viability of not only L1210S, but of L1210R cells as well.. Conclusion: Combined treatment with photoexcited C60 and cisplatin allowed to decrease effective concentration of cisplatin against parental L1210 cells and to increase sensibility of resistant cells to the drug.

C60 fullerene and its nanocomplexes with anticancer drugs modulate circulating phagocyte functions and dramatically increase ROS generation in transformed monocytes

“…Based on our previous experience, in vivo anticancer effects of C 60 fullerene and C 60 + Dox nanocomplexes are accompanied by the increase of macrophage oxygen-dependent cytotoxicity toward authologic tumor cells (Prylutska et al 2015 ). In addition, our previous results revealed direct toxic effects of C 60 fullerene and its nanocomplexes with anticancer drugs on transformed leukocytes including myelocytic cells (Panchuk et al 2015 ; Scharff et al 2008 ; Franskevych et al 2015 ).…”

Activation of store – operated Ca(2+) entry in cisplatin resistant leukemic cells after treatment with photoexcited fullerene C(60) and cisplatin

“…As it was earlier shown by us, a substantial increase of [Ca 2+ ]cyt in leukemic cells was detected 3 h after combined treatment with photoexcited C 60 and cisplatin [21]. To investigate the possible reason of this event Ca 2+ liberation from intracellular stores into the cytosol of leukemic cells was examined.…”

“…The both cell lines were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS, Sigma-Aldrich, Germany), 50 μg/ml penicillin and 100 μg/ml streptomycin at 37 °C in a 5% CO 2 humidified atmosphere. Cisplatin in a range of 0.1-10 µg/ml was shown to decrease the viability of L1210 in a dose dependent manner up to 90% during 72 h incubation with no effect on L1210R cells [21].…”

“…Combined treatment of leukemic cells with photoexcited fullerene C 60 and 1 µg/ml cisplatin allowed us to enhance cytotoxic effect and to accelerate cell death of both sensitive and resistant to cisplatin cells as compared with each agent to be used alone [20,21], but the biochemical mechanisms of this effect need further elucidation. A substantial increase of [Ca 2+ ] cyt in leukemic cells which was detected 3 h after combined treatment with photoexcited C 60 and cisplatin [21] could be one of the determining factors in this effect.…”

Mode of photoexcited C60 fullerene involvement in potentiating cisplatin toxicity against drug-resistant L1210 cells

“…In the previous studies, we confirmed fullerene C 60 nanoparticles penetration into leukemic L1210 cells and demonstrated photoinduced cytotoxicity of accumulated C 60 determined by ROS production. 21 The possibility to decrease substantially the viability of cisplatin-resistant L1210R cells by combined treatment with photoexcited C 60 fullerene and cisplatin was also shown, 22 but the mechanisms of this phenomenon still need further investigation.…”