ANTI-MYELOMA EFFECT OF CANNABINOIDS
(Abstract release date: 05/19/16)
EHA Library. Antonio Perez-Simon J. 06/09/16; 132798; E1249
Dr. Jose Antonio Perez-Simon
Contributions
Contributions
Abstract
Abstract: E1249
Type: Eposter Presentation
Background
It is well studied the antiproliferative and proapoptotic effects of cannabinoids in neoplasias of the central nervous system, where the cannabinoid receptor type 1 (CB1) exhibits the highest levels of expression. In contrast, the cannabinoid receptor type 2 (CB) is found also exclusively in the hematopoietic and immune system. Despite this, the potential effect of cannabinoids on hematologic malignancies has been poorly determined.
Aims
Our purpose is to investigate the anti-tumor effect, both in vitro and in vivo, of different cannabinoids in multiple myeloma (MM) and know the main signaling pathways implicated in the effect of cannabinoids.
Methods
We evaluated the effect of five cannabinoid compounds in cell viability of six different human multiple myeloma cell lines, primary myeloma plasma cells and healthy primary cells from patients and donors. We studied the involvement of the main signaling pathways in the effect of cannabinoid as well as the expression of capases and some proteins of family Bcl-2 and also of the SPT enzyme by Western-blot. We used selective antagonists of cannabinoid receptors to know if the effect antiproliferative of tested cannabinoids is mediated by CB2. The role of ceramide was examined by immunohistochemistry and by pharmacological inhibition of the synthesis route. In addition we evaluated the synergism of the combination of cannabinoids with antimyeloma agents, such as dexamethasone and melphalan. Finally, we evaluated the effect of cannabinoids in MM xenograft models.
Results
We demonstrate that cannabinoids induce a selective apoptosis in myeloma cell lines and in primary malignant plasma cells from MM patients, without affecting the viability of normal cells from healthy donors, including hematopoietic stem cells. This antiproliferative effect is mediated by activation of caspases, mainly caspase 2, and is partially prevented by a pan-caspase inhibitor. Cannabinoid-induced apoptosis was correlated with an increased expression of Bax and Bak and a decrease of Bcl-xL and Mcl-1. In addition, cannabinoid treatment induced a biphasic response of Akt/PKB and significantly increased the levels of ceramide in MM cells. Remarkably, the blockade of ceramide synthesis prevented cannabinoid-induced apoptosis, indicating that ceramides play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Furthermore, blockage of the cannabinoid receptor CB2 also inhibited cannabinoid induced apoptosis. Cannabinoid WIN-55 enhanced the antimyeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo.
Conclusion
Our findings suggest that cannabinoids induce a selective apoptosis in tumor cells without adverse effects and thus they may be considered as potential therapeutic agents in the treatment of multiple myeloma.
Session topic: E-poster
Keyword(s): Lipid metabolism, Myeloma
Type: Eposter Presentation
Background
It is well studied the antiproliferative and proapoptotic effects of cannabinoids in neoplasias of the central nervous system, where the cannabinoid receptor type 1 (CB1) exhibits the highest levels of expression. In contrast, the cannabinoid receptor type 2 (CB) is found also exclusively in the hematopoietic and immune system. Despite this, the potential effect of cannabinoids on hematologic malignancies has been poorly determined.
Aims
Our purpose is to investigate the anti-tumor effect, both in vitro and in vivo, of different cannabinoids in multiple myeloma (MM) and know the main signaling pathways implicated in the effect of cannabinoids.
Methods
We evaluated the effect of five cannabinoid compounds in cell viability of six different human multiple myeloma cell lines, primary myeloma plasma cells and healthy primary cells from patients and donors. We studied the involvement of the main signaling pathways in the effect of cannabinoid as well as the expression of capases and some proteins of family Bcl-2 and also of the SPT enzyme by Western-blot. We used selective antagonists of cannabinoid receptors to know if the effect antiproliferative of tested cannabinoids is mediated by CB2. The role of ceramide was examined by immunohistochemistry and by pharmacological inhibition of the synthesis route. In addition we evaluated the synergism of the combination of cannabinoids with antimyeloma agents, such as dexamethasone and melphalan. Finally, we evaluated the effect of cannabinoids in MM xenograft models.
Results
We demonstrate that cannabinoids induce a selective apoptosis in myeloma cell lines and in primary malignant plasma cells from MM patients, without affecting the viability of normal cells from healthy donors, including hematopoietic stem cells. This antiproliferative effect is mediated by activation of caspases, mainly caspase 2, and is partially prevented by a pan-caspase inhibitor. Cannabinoid-induced apoptosis was correlated with an increased expression of Bax and Bak and a decrease of Bcl-xL and Mcl-1. In addition, cannabinoid treatment induced a biphasic response of Akt/PKB and significantly increased the levels of ceramide in MM cells. Remarkably, the blockade of ceramide synthesis prevented cannabinoid-induced apoptosis, indicating that ceramides play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Furthermore, blockage of the cannabinoid receptor CB2 also inhibited cannabinoid induced apoptosis. Cannabinoid WIN-55 enhanced the antimyeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo.
Conclusion
Our findings suggest that cannabinoids induce a selective apoptosis in tumor cells without adverse effects and thus they may be considered as potential therapeutic agents in the treatment of multiple myeloma.
Session topic: E-poster
Keyword(s): Lipid metabolism, Myeloma
Abstract: E1249
Type: Eposter Presentation
Background
It is well studied the antiproliferative and proapoptotic effects of cannabinoids in neoplasias of the central nervous system, where the cannabinoid receptor type 1 (CB1) exhibits the highest levels of expression. In contrast, the cannabinoid receptor type 2 (CB) is found also exclusively in the hematopoietic and immune system. Despite this, the potential effect of cannabinoids on hematologic malignancies has been poorly determined.
Aims
Our purpose is to investigate the anti-tumor effect, both in vitro and in vivo, of different cannabinoids in multiple myeloma (MM) and know the main signaling pathways implicated in the effect of cannabinoids.
Methods
We evaluated the effect of five cannabinoid compounds in cell viability of six different human multiple myeloma cell lines, primary myeloma plasma cells and healthy primary cells from patients and donors. We studied the involvement of the main signaling pathways in the effect of cannabinoid as well as the expression of capases and some proteins of family Bcl-2 and also of the SPT enzyme by Western-blot. We used selective antagonists of cannabinoid receptors to know if the effect antiproliferative of tested cannabinoids is mediated by CB2. The role of ceramide was examined by immunohistochemistry and by pharmacological inhibition of the synthesis route. In addition we evaluated the synergism of the combination of cannabinoids with antimyeloma agents, such as dexamethasone and melphalan. Finally, we evaluated the effect of cannabinoids in MM xenograft models.
Results
We demonstrate that cannabinoids induce a selective apoptosis in myeloma cell lines and in primary malignant plasma cells from MM patients, without affecting the viability of normal cells from healthy donors, including hematopoietic stem cells. This antiproliferative effect is mediated by activation of caspases, mainly caspase 2, and is partially prevented by a pan-caspase inhibitor. Cannabinoid-induced apoptosis was correlated with an increased expression of Bax and Bak and a decrease of Bcl-xL and Mcl-1. In addition, cannabinoid treatment induced a biphasic response of Akt/PKB and significantly increased the levels of ceramide in MM cells. Remarkably, the blockade of ceramide synthesis prevented cannabinoid-induced apoptosis, indicating that ceramides play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Furthermore, blockage of the cannabinoid receptor CB2 also inhibited cannabinoid induced apoptosis. Cannabinoid WIN-55 enhanced the antimyeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo.
Conclusion
Our findings suggest that cannabinoids induce a selective apoptosis in tumor cells without adverse effects and thus they may be considered as potential therapeutic agents in the treatment of multiple myeloma.
Session topic: E-poster
Keyword(s): Lipid metabolism, Myeloma
Type: Eposter Presentation
Background
It is well studied the antiproliferative and proapoptotic effects of cannabinoids in neoplasias of the central nervous system, where the cannabinoid receptor type 1 (CB1) exhibits the highest levels of expression. In contrast, the cannabinoid receptor type 2 (CB) is found also exclusively in the hematopoietic and immune system. Despite this, the potential effect of cannabinoids on hematologic malignancies has been poorly determined.
Aims
Our purpose is to investigate the anti-tumor effect, both in vitro and in vivo, of different cannabinoids in multiple myeloma (MM) and know the main signaling pathways implicated in the effect of cannabinoids.
Methods
We evaluated the effect of five cannabinoid compounds in cell viability of six different human multiple myeloma cell lines, primary myeloma plasma cells and healthy primary cells from patients and donors. We studied the involvement of the main signaling pathways in the effect of cannabinoid as well as the expression of capases and some proteins of family Bcl-2 and also of the SPT enzyme by Western-blot. We used selective antagonists of cannabinoid receptors to know if the effect antiproliferative of tested cannabinoids is mediated by CB2. The role of ceramide was examined by immunohistochemistry and by pharmacological inhibition of the synthesis route. In addition we evaluated the synergism of the combination of cannabinoids with antimyeloma agents, such as dexamethasone and melphalan. Finally, we evaluated the effect of cannabinoids in MM xenograft models.
Results
We demonstrate that cannabinoids induce a selective apoptosis in myeloma cell lines and in primary malignant plasma cells from MM patients, without affecting the viability of normal cells from healthy donors, including hematopoietic stem cells. This antiproliferative effect is mediated by activation of caspases, mainly caspase 2, and is partially prevented by a pan-caspase inhibitor. Cannabinoid-induced apoptosis was correlated with an increased expression of Bax and Bak and a decrease of Bcl-xL and Mcl-1. In addition, cannabinoid treatment induced a biphasic response of Akt/PKB and significantly increased the levels of ceramide in MM cells. Remarkably, the blockade of ceramide synthesis prevented cannabinoid-induced apoptosis, indicating that ceramides play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Furthermore, blockage of the cannabinoid receptor CB2 also inhibited cannabinoid induced apoptosis. Cannabinoid WIN-55 enhanced the antimyeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo.
Conclusion
Our findings suggest that cannabinoids induce a selective apoptosis in tumor cells without adverse effects and thus they may be considered as potential therapeutic agents in the treatment of multiple myeloma.
Session topic: E-poster
Keyword(s): Lipid metabolism, Myeloma
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