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Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

Suzuki M, Chiwaki F, Sawada Y, Ashikawa M, Aoyagi K, Fujita T, Yanagihara K, Komatsu M, Narita M, Suzuki T, Nagase H, Kushima R, Sakamoto H, Fukagawa T, Katai H, Nakagama H, Yoshida T, Uezono Y, Sasaki H - PLoS ONE (2015)

Bottom Line: We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs).The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc.These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT
The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

No MeSH data available.


Related in: MedlinePlus

Blockade of OGF signaling by MNTX increased the growth of diffuse-type GC cells co-cultured with mesothelial cells.A, RT-PCR analyses of Penk and Ogfr, in mouse mesothelial cells (1Cs-mM). B, schematic illustration of the system for co-culture of 60As6-GFP and 1Cs-mM. C, Growth of 60As6-GFP cells co-cultured with 1Cs-mM cells in the presence or absence of MNTX (10-5 M) for 72 h. Scale bar, 20 μm. D, the growth of 60As6-GFP cells was calculated (mean ± SD, n = 3 each, *p<0.05). E, growth of the diffuse-type GC cell line 60As6 cells, the intestinal-type GC cell line HSC-42 cells, the pancreatic cancer cell line PANC-1 cells, and primary cultured GC cells derived from the ascites of a patient NSC-16C cells treated with Doc (10-9 M) or a vehicle for 48 h, and subsequently treated with Doc, Doc/MNTX (10-6 M) or a vehicle for 48 h. Cells were counted with a hemacytometer (mean ± SD, n = 4 each, *p<0.05, vs. control, #p<0.05, Doc vs. Doc/MNTX).
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pone.0123407.g003: Blockade of OGF signaling by MNTX increased the growth of diffuse-type GC cells co-cultured with mesothelial cells.A, RT-PCR analyses of Penk and Ogfr, in mouse mesothelial cells (1Cs-mM). B, schematic illustration of the system for co-culture of 60As6-GFP and 1Cs-mM. C, Growth of 60As6-GFP cells co-cultured with 1Cs-mM cells in the presence or absence of MNTX (10-5 M) for 72 h. Scale bar, 20 μm. D, the growth of 60As6-GFP cells was calculated (mean ± SD, n = 3 each, *p<0.05). E, growth of the diffuse-type GC cell line 60As6 cells, the intestinal-type GC cell line HSC-42 cells, the pancreatic cancer cell line PANC-1 cells, and primary cultured GC cells derived from the ascites of a patient NSC-16C cells treated with Doc (10-9 M) or a vehicle for 48 h, and subsequently treated with Doc, Doc/MNTX (10-6 M) or a vehicle for 48 h. Cells were counted with a hemacytometer (mean ± SD, n = 4 each, *p<0.05, vs. control, #p<0.05, Doc vs. Doc/MNTX).

Mentions: The microenvironment for the peritoneal metastasis of diffuse-type GC is made up of mesothelial cells and myofibroblasts [14–16]. The first surface that free tumor cells encounter is the innermost layer of the peritoneum, the mesothelium. The mesothelium forms a cellular monolayer supported by a basement membrane. The adherence of tumor cells to the mesothelium is the second step in the metastatic cascade, which temporarily arrests the tumor cells to their eventual site of metastasis [17]. A recent study suggested that these cells are functionally organized to promote the survival of tumor cells in the host [18]. Interestingly, our originally established mouse mesothelial cell line 1Cs-mM (Fig 3A) also expresses Penk mRNA. Thus, we next investigated whether OGF released by mesothelial cells suppressed tumor cell growth using a co-culture cell system of GFP-expressing 60As6 (60As6-GFP) cells and a mouse mesothelial cell line, 1Cs-mM cells (Fig 3B). Twenty-four hours after 1Cs-mM cells were plated, 60As6-GFP cells were seeded at a 1: 4 (60As6-GFP: 1Cs-mM) ratio and treated with MNTX or vehicle for 72 h. As expected, treatment with MNTX significantly increased 60As6-GFP cell growth in this system (144.0 ± 23.3%, Fig 3C and 3D), indicating that peritoneal mesothelium-derived OGF can also arrest tumor cell growth. Myofibroblasts or carcinoma-associated fibroblasts are the most abundant cell type in the primary tumor and have been shown to promote resistance to anti-tumor drugs [19]. The mouse fibroblast cell line NIH3T3 also expresses Penk mRNA (S6A Fig). As with mesothelial cells, treatment with MNTX was associated with a significant increase in the growth of 60As6-GFP cells in the co-culture system with NIH3T3 cells (122.5 ± 12.6%, S6B and S6C Fig).


Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

Suzuki M, Chiwaki F, Sawada Y, Ashikawa M, Aoyagi K, Fujita T, Yanagihara K, Komatsu M, Narita M, Suzuki T, Nagase H, Kushima R, Sakamoto H, Fukagawa T, Katai H, Nakagama H, Yoshida T, Uezono Y, Sasaki H - PLoS ONE (2015)

Blockade of OGF signaling by MNTX increased the growth of diffuse-type GC cells co-cultured with mesothelial cells.A, RT-PCR analyses of Penk and Ogfr, in mouse mesothelial cells (1Cs-mM). B, schematic illustration of the system for co-culture of 60As6-GFP and 1Cs-mM. C, Growth of 60As6-GFP cells co-cultured with 1Cs-mM cells in the presence or absence of MNTX (10-5 M) for 72 h. Scale bar, 20 μm. D, the growth of 60As6-GFP cells was calculated (mean ± SD, n = 3 each, *p<0.05). E, growth of the diffuse-type GC cell line 60As6 cells, the intestinal-type GC cell line HSC-42 cells, the pancreatic cancer cell line PANC-1 cells, and primary cultured GC cells derived from the ascites of a patient NSC-16C cells treated with Doc (10-9 M) or a vehicle for 48 h, and subsequently treated with Doc, Doc/MNTX (10-6 M) or a vehicle for 48 h. Cells were counted with a hemacytometer (mean ± SD, n = 4 each, *p<0.05, vs. control, #p<0.05, Doc vs. Doc/MNTX).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390307&req=5

pone.0123407.g003: Blockade of OGF signaling by MNTX increased the growth of diffuse-type GC cells co-cultured with mesothelial cells.A, RT-PCR analyses of Penk and Ogfr, in mouse mesothelial cells (1Cs-mM). B, schematic illustration of the system for co-culture of 60As6-GFP and 1Cs-mM. C, Growth of 60As6-GFP cells co-cultured with 1Cs-mM cells in the presence or absence of MNTX (10-5 M) for 72 h. Scale bar, 20 μm. D, the growth of 60As6-GFP cells was calculated (mean ± SD, n = 3 each, *p<0.05). E, growth of the diffuse-type GC cell line 60As6 cells, the intestinal-type GC cell line HSC-42 cells, the pancreatic cancer cell line PANC-1 cells, and primary cultured GC cells derived from the ascites of a patient NSC-16C cells treated with Doc (10-9 M) or a vehicle for 48 h, and subsequently treated with Doc, Doc/MNTX (10-6 M) or a vehicle for 48 h. Cells were counted with a hemacytometer (mean ± SD, n = 4 each, *p<0.05, vs. control, #p<0.05, Doc vs. Doc/MNTX).
Mentions: The microenvironment for the peritoneal metastasis of diffuse-type GC is made up of mesothelial cells and myofibroblasts [14–16]. The first surface that free tumor cells encounter is the innermost layer of the peritoneum, the mesothelium. The mesothelium forms a cellular monolayer supported by a basement membrane. The adherence of tumor cells to the mesothelium is the second step in the metastatic cascade, which temporarily arrests the tumor cells to their eventual site of metastasis [17]. A recent study suggested that these cells are functionally organized to promote the survival of tumor cells in the host [18]. Interestingly, our originally established mouse mesothelial cell line 1Cs-mM (Fig 3A) also expresses Penk mRNA. Thus, we next investigated whether OGF released by mesothelial cells suppressed tumor cell growth using a co-culture cell system of GFP-expressing 60As6 (60As6-GFP) cells and a mouse mesothelial cell line, 1Cs-mM cells (Fig 3B). Twenty-four hours after 1Cs-mM cells were plated, 60As6-GFP cells were seeded at a 1: 4 (60As6-GFP: 1Cs-mM) ratio and treated with MNTX or vehicle for 72 h. As expected, treatment with MNTX significantly increased 60As6-GFP cell growth in this system (144.0 ± 23.3%, Fig 3C and 3D), indicating that peritoneal mesothelium-derived OGF can also arrest tumor cell growth. Myofibroblasts or carcinoma-associated fibroblasts are the most abundant cell type in the primary tumor and have been shown to promote resistance to anti-tumor drugs [19]. The mouse fibroblast cell line NIH3T3 also expresses Penk mRNA (S6A Fig). As with mesothelial cells, treatment with MNTX was associated with a significant increase in the growth of 60As6-GFP cells in the co-culture system with NIH3T3 cells (122.5 ± 12.6%, S6B and S6C Fig).

Bottom Line: We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs).The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc.These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT
The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

No MeSH data available.


Related in: MedlinePlus