Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer Export

@article{citeulike:2696525, abstract = {Although multidrug resistance (MDR) is known to develop through a variety of molecular mechanisms within the tumor cell, many tend to converge toward the alteration of apoptotic signaling. The enzyme glucosylceramide synthase (GCS), responsible for bioactivation of the proapoptotic mediator ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumor types and has been implicated in cell survival in the presence of chemotherapy. The purpose of this study was to investigate the therapeutic strategy of coadministering ceramide with paclitaxel, a commonly used chemotherapeutic agent, in an attempt to restore apoptotic signaling and overcome MDR in the human ovarian cancer cell line SKOV3. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were used to encapsulate and deliver the therapeutic agents for enhanced efficacy. Results show that indeed the cotherapy eradicates the complete population of MDR cancer cells when they are treated at their IC50 dose of paclitaxel. More interestingly, when the cotherapy was combined with the properties of nanoparticle drug delivery, the MDR cells can be resensitized to a dose of paclitaxel near the IC50 of non-MDR (drug sensitive) cells, indicating a 100-fold increase in chemosensitization via this approach. Molecular analysis of activity verified the hypothesis that the efficacy of this therapeutic approach is indeed due to a restoration in apoptotic signaling, although the beneficial properties of PEO-PCL nanoparticle delivery seemed to enhance the therapeutic success even further, showing the promising potential for the clinical use of this therapeutic strategy to overcome MDR. [Cancer Res 2007;67(10):484350] 10.1158/0008-5472.CAN-06-1648}, author = {van Vlerken, Lilian E. and Duan, Zhenfeng and Seiden, Michael V. and Amiji, Mansoor M.}, citeulike-article-id = {2696525}, citeulike-linkout-0 = {http://dx.doi.org/10.1158/0008-5472.CAN-06-1648}, citeulike-linkout-1 = {http://cancerres.aacrjournals.org/cgi/content/abstract/67/10/4843}, day = {15}, doi = {10.1158/0008-5472.CAN-06-1648}, journal = {Cancer Res}, keywords = {apoptosis, ccne-grant, ceramide, multi-drug-resistance, neu-ccne, oxide-modified-polyepsilon-caprolactone, paclitaxel, polyethylene, tamoxifen, verapamil}, month = {May}, number = {10}, pages = {4843--4850}, posted-at = {2008-04-21 15:24:19}, priority = {4}, title = {Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-06-1648}, volume = {67}, year = {2007} }

TY - JOUR ID - citeulike:2696525 L3 - citeulike-article-id:2696525 N2 - Although multidrug resistance (MDR) is known to develop through a variety of molecular mechanisms within the tumor cell, many tend to converge toward the alteration of apoptotic signaling. The enzyme glucosylceramide synthase (GCS), responsible for bioactivation of the proapoptotic mediator ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumor types and has been implicated in cell survival in the presence of chemotherapy. The purpose of this study was to investigate the therapeutic strategy of coadministering ceramide with paclitaxel, a commonly used chemotherapeutic agent, in an attempt to restore apoptotic signaling and overcome MDR in the human ovarian cancer cell line SKOV3. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were used to encapsulate and deliver the therapeutic agents for enhanced efficacy. Results show that indeed the cotherapy eradicates the complete population of MDR cancer cells when they are treated at their IC50 dose of paclitaxel. More interestingly, when the cotherapy was combined with the properties of nanoparticle drug delivery, the MDR cells can be resensitized to a dose of paclitaxel near the IC50 of non-MDR (drug sensitive) cells, indicating a 100-fold increase in chemosensitization via this approach. Molecular analysis of activity verified the hypothesis that the efficacy of this therapeutic approach is indeed due to a restoration in apoptotic signaling, although the beneficial properties of PEO-PCL nanoparticle delivery seemed to enhance the therapeutic success even further, showing the promising potential for the clinical use of this therapeutic strategy to overcome MDR. [Cancer Res 2007;67(10):484350] 10.1158/0008-5472.CAN-06-1648 IS - 10 JF - Cancer Res EP - 4850 TI - Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer VL - 67 SP - 4843 KW - apoptosis KW - ccne-grant KW - ceramide KW - multi-drug-resistance KW - neu-ccne KW - oxide-modified-polyepsilon-caprolactone KW - paclitaxel KW - polyethylene KW - tamoxifen KW - verapamil AU - van Vlerken, Lilian AU - Duan, Zhenfeng AU - Seiden, Michael AU - Amiji, Mansoor PY - 2007/05/15/ UR - http://dx.doi.org/10.1158/0008-5472.CAN-06-1648 ER -