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Editor’s Choice : Sildenafil Enhances the Anticancer Activity of Paclitaxel in an ABCB1-Mediated Multidrug Resistance Xenograft Mouse Model
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Abstract: The overexpression of ATP-binding cassette (ABC) transporters can produce multidrug resistance (MDR) in cancer cells. Previous in vitro studies from our group reported that sildenafil significantly inhibits the efflux function of the ABCB1/P-glycoprotein transporter in vitro. This investigation examined the effect of sildenafil on the ABCB1 transporter-mediated MDR in vivo. A nude mouse ABCB1 overexpressing-xenograft model was used to examine the effect of sildenafil in vivo. The concentration of paclitaxel in tumors and plasma was analyzed using high performance liquid chromatography (HPLC). Sildenafil attenuated tumor growth synergistically, and this occurred without significant weight loss or other overt phenotypic changes. The action of sildenafil can be attributed to the inhibition of the ABCB1-mediated drug efflux, thereby increasing the concentration of paclitaxel in ABCB1-overexpressing tumors. The potentiation of the pharmacologic action of paclitaxel by sildenafil suggests that it may be useful in treating cancers that overexpress the ABCB1 transporter. Keywords: ABCB1, multidrug resistance, paclitaxel, sildenafil.Download Full Article |
Editor’s Choice : Surface Functionalization of Gold Nanoparticles for Simultaneous Suppression of Cancer Stem Cells and Cancer Cells
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Abstract: Surface functionalization of gold nanoparticles is designed for simultaneous suppression of cancer stem cells and cancer cells. The fundamental mechanism of the simultaneous suppression is based on the blocking against DNA polymerase, DNA helicase and RNA polymerase by positively charged gold nanoparticles introduced into nucleuses. In addition, applications of physical fields (ultrasound, X-ray or electromagnetic wave) will enhance the suppression effects of the cancer cells by interactions between gold nanoparticles and physical fields. It is predicted theoretically that the surface functionalization of gold nanoparticle is promising for radical treatments of cancers. Keywords: Gold nanoparticles, cancer cells, cancer stem cells, DNA, chromosome, histones, DNA helicase, DNA polymerase, RNA polymerase.Download Full Article |
Editor’s Choice : The Overexpression of ABCG2 Reduces the Efficacy of Volasertib (BI 6727) and GSK641364 in Human S1-M1-80 Colon Carcinoma Cells
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Abstract: The polo-like kinase 1 (Plk1) is one of the key regulators in cell cycle progression. Plk1 is overexpressed in many types of cancer and promotes the proliferation of cancer cells. Inhibition of Plk1 activity induces G2/M cell cycle arrest and reduces cancer cell viability. Volasertib and GSK461364 are selective inhibitors of Plk1, active against a wide range of tumor cells at nanomolar concentrations. In this study, while examining the effectiveness of Plk1 inhibitors against multiple human colon cancer cell lines, we discovered that the overexpression of ATP-binding cassette (ABC) drug transporter ABCG2 in human S1-M1-80 colon cancer cells confers resistance to volasertib and GSK461364. Moreover, we found that ABCG2-transfected HEK293 cells were also resistant to both Plk1 inhibitors. We revealed that volasertib and GSK461364 inhibited the function of ABCG2 in a concentration dependent manner, and had no significant effect on the protein expression of ABCG2. More importantly, we showed that the G2/M cell cycle arrest induced by volasertib or GSK461364 was significantly reduced in S1-M1-80 cells, and that ABCG2-mediated drug resistance to Plk1 inhibitors can be restored by inhibition of ABCG2 function. Therefore, the development of ABCG2-mediated drug resistance to volasertib and GSK461364 in cancer clearly present a significant therapeutic challenge, and a better treatment strategy should be further investigated. Keywords: ABCG2, multidrug resistance, Polo-like kinase 1, volasertib, GSK641364.Download Full Article |
Editor’s Choice : B5H7, a Morpholine Derivative of 23-Hydroxybetulinic Acid, Reverses Doxorubicin Resistance in HepG2/ADM
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Abstract: Multidrug resistance (MDR) is the major cause of the failure of cancer chemotherapy. Development of MDR reversers is an important strategy to improve the efficacy of cancer chemotherapy. Here, we have found a morpholine derivative of 23-hydroxybetulinic acid, B5H7, with a reversal effect on MDR cancer cells. Our studies showed that B5H7 enhanced cytotoxicity of doxorubicin, but no cisplatin in MDR cancer cells HepG2/ADM. And we found that B5H7 not only increased the intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123, but also reduced the efflux of rhodamine123 in HepG2/ADM cells. Further studies showed B5H7 did not alter the protein level of P-glycoprotein and it also had no effect on P-glycoprotein ATPase activity. Taken together, we have found that B5H7 could reverse doxorubicin resistance in HepG2/ADM cells by inhibiting the transport function of P-glycoprotein. These findings contribute to developing B5H7 as an adjuvant to anticancer chemotherapy with doxorubicin. Keywords: Doxorubicin resistance, ABC transporter, P-glycoprotein, 23-HBA derivative B5H7, HepG2/ADM.Download Full Article |
