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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

Combined use of Doc and MNTX significantly prolonged survival and alleviated abdominal pain in model mice.A, survival curves of middle-phase peritoneal metastasis model mice treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, #p<0.05, Doc vs. Doc/MNTX). Drug administration was started 7 days after the inoculation of 60As6-Luc cells. Mice were treated with Doc or a combination of Doc and MNTX 2 times a week until the endpoint criteria were met. B, visceral pain-related behavior of peritoneal metastasis model mice. Visceral pain-related behavior was assessed in terms of the degree of hunching and the time spent hunching before each drug treatment at 35 days after the inoculation of 60As6-Luc cells (mean ± SD, n = 14 each, *p<0.05). C, survival curves of peritoneal metastasis mice of OGFR-shRNA transfected 60As6 cells (OGFR-KD) treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, no significance in Doc vs. Doc/MNTX).
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pone.0123407.g005: Combined use of Doc and MNTX significantly prolonged survival and alleviated abdominal pain in model mice.A, survival curves of middle-phase peritoneal metastasis model mice treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, #p<0.05, Doc vs. Doc/MNTX). Drug administration was started 7 days after the inoculation of 60As6-Luc cells. Mice were treated with Doc or a combination of Doc and MNTX 2 times a week until the endpoint criteria were met. B, visceral pain-related behavior of peritoneal metastasis model mice. Visceral pain-related behavior was assessed in terms of the degree of hunching and the time spent hunching before each drug treatment at 35 days after the inoculation of 60As6-Luc cells (mean ± SD, n = 14 each, *p<0.05). C, survival curves of peritoneal metastasis mice of OGFR-shRNA transfected 60As6 cells (OGFR-KD) treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, no significance in Doc vs. Doc/MNTX).

Mentions: Conventional therapeutic modalities have failed to improve survival or outcomes among patients with peritoneal dissemination. Recently, intraperitoneal chemotherapy, which is the direct application of chemotherapeutic agents to macro/microscopic tumor seeding, has been considered to be a promising method for reducing the incidence of peritoneal dissemination [20, 21]. Therefore, we established mouse models for the intraperitoneal administration of Doc, which corresponded to 3 different phases (early, middle, and late) in the progression of peritoneal dissemination (Fig 4A–4C). The xenografts of 60As6 as well as clinical samples (Fig 1A) showed a high proportion of Ki-67-negative non-proliferating tumor cells (Fig 4D). A quite low dose of Doc (0.5 mg/kg) was used in these models, and therefore the toxicity of Doc was considered to be extremely low. Among the 3 different models, we selected the middle-phase model, which has characteristics similar to those of patients with multiple small tumor nodules that cannot be detected by a computed tomography scan. By in vivo imaging with luciferase-expressing 60As6 cells (60As6Luc) [22], representative chronological tumor growth was observed in the mouse peritoneal cavity treated with saline, Doc or Doc/MNTX (0.3 mg/kg) (Fig 4E). Beginning on day 7 after inoculation, the mice were divided into 4 groups based on photon counts. The mice were then treated intraperitoneally with the above reagents twice weekly until the endpoint criteria were met. In the saline-treated mice, tumor progression in the peritoneal cavity was observed on day 14 after inoculation. A marked increase in the volume of ascites was noted and moribund mice were observed around day 28. A high concentration of OGF was observed in mouse ascites (S7A Fig) as well as in the GC patients (S3B Fig). On the other hand, mice that had been treated with Doc or Doc/MNTX tended to be stable with slower tumor growth up to day 28. No ascites formation was noted in any of the mice. Consistent with these results, the intraperitoneal administration of Doc or Doc/MNTX clearly prolonged survival compared with that in saline-treated mice (Fig 5A). Notably, the survival time of Doc/MNTX-treated mice was significantly greater than that of Doc-treated mice (Fig 5A). Conversely, the combined use of Doc and OGF was likely to shorten survival relative to that with Doc alone (S7B Fig). There was no difference in survival time between MNTX-treated mice and saline-treated mice (S7C Fig). In accordance with these effects, visceral pain-related hunching behavior on day 35 after inoculation was apparently decreased in Doc/MNTX-treated mice compared with Doc-treated mice (Fig 5B). Importantly, a booster effect of MNTX with respect to Doc was not observed in an OGFR shRNA-transfectant, 60As6-OGFR-KD, in vivo (Fig 5C). The eradication of free tumor cells and suppression of the formation of multiple small tumor nodules on the membranes of the abdomen are major challenges in the treatment of peritoneal metastasis. To clarify the effects of Doc/MNTX in this regard, we monitored 60As6-GFP cells on the membranes of the abdomen. In mice treated with saline, several 1–3 mm tumors studding the mesentery adjacent to the bowel were observed on day 31 after inoculation (Fig 6A). In mice that had been treated with Doc or Doc/MNTX, fewer tumor nodules were noted on day 49 (Fig 6A, white box in the upper region of the cecum). However, isolated tumor cells and small tumor cell spheroids, which were located in the vascular bed of the mesentery, were found only in Doc-treated mice (Fig 6A). Based on the results of microscopic observation, there were significantly fewer single cells and spheroids in Doc/MNTX-treated mice than in Doc-treated mice (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)

Combined use of Doc and MNTX significantly prolonged survival and alleviated abdominal pain in model mice.A, survival curves of middle-phase peritoneal metastasis model mice treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, #p<0.05, Doc vs. Doc/MNTX). Drug administration was started 7 days after the inoculation of 60As6-Luc cells. Mice were treated with Doc or a combination of Doc and MNTX 2 times a week until the endpoint criteria were met. B, visceral pain-related behavior of peritoneal metastasis model mice. Visceral pain-related behavior was assessed in terms of the degree of hunching and the time spent hunching before each drug treatment at 35 days after the inoculation of 60As6-Luc cells (mean ± SD, n = 14 each, *p<0.05). C, survival curves of peritoneal metastasis mice of OGFR-shRNA transfected 60As6 cells (OGFR-KD) treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, no significance in Doc vs. Doc/MNTX).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4390307&req=5

pone.0123407.g005: Combined use of Doc and MNTX significantly prolonged survival and alleviated abdominal pain in model mice.A, survival curves of middle-phase peritoneal metastasis model mice treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, #p<0.05, Doc vs. Doc/MNTX). Drug administration was started 7 days after the inoculation of 60As6-Luc cells. Mice were treated with Doc or a combination of Doc and MNTX 2 times a week until the endpoint criteria were met. B, visceral pain-related behavior of peritoneal metastasis model mice. Visceral pain-related behavior was assessed in terms of the degree of hunching and the time spent hunching before each drug treatment at 35 days after the inoculation of 60As6-Luc cells (mean ± SD, n = 14 each, *p<0.05). C, survival curves of peritoneal metastasis mice of OGFR-shRNA transfected 60As6 cells (OGFR-KD) treated with saline, Doc, or Doc/MNTX (0.3 mg/kg) (n = 5, *p<0.05, vs. saline, no significance in Doc vs. Doc/MNTX).
Mentions: Conventional therapeutic modalities have failed to improve survival or outcomes among patients with peritoneal dissemination. Recently, intraperitoneal chemotherapy, which is the direct application of chemotherapeutic agents to macro/microscopic tumor seeding, has been considered to be a promising method for reducing the incidence of peritoneal dissemination [20, 21]. Therefore, we established mouse models for the intraperitoneal administration of Doc, which corresponded to 3 different phases (early, middle, and late) in the progression of peritoneal dissemination (Fig 4A–4C). The xenografts of 60As6 as well as clinical samples (Fig 1A) showed a high proportion of Ki-67-negative non-proliferating tumor cells (Fig 4D). A quite low dose of Doc (0.5 mg/kg) was used in these models, and therefore the toxicity of Doc was considered to be extremely low. Among the 3 different models, we selected the middle-phase model, which has characteristics similar to those of patients with multiple small tumor nodules that cannot be detected by a computed tomography scan. By in vivo imaging with luciferase-expressing 60As6 cells (60As6Luc) [22], representative chronological tumor growth was observed in the mouse peritoneal cavity treated with saline, Doc or Doc/MNTX (0.3 mg/kg) (Fig 4E). Beginning on day 7 after inoculation, the mice were divided into 4 groups based on photon counts. The mice were then treated intraperitoneally with the above reagents twice weekly until the endpoint criteria were met. In the saline-treated mice, tumor progression in the peritoneal cavity was observed on day 14 after inoculation. A marked increase in the volume of ascites was noted and moribund mice were observed around day 28. A high concentration of OGF was observed in mouse ascites (S7A Fig) as well as in the GC patients (S3B Fig). On the other hand, mice that had been treated with Doc or Doc/MNTX tended to be stable with slower tumor growth up to day 28. No ascites formation was noted in any of the mice. Consistent with these results, the intraperitoneal administration of Doc or Doc/MNTX clearly prolonged survival compared with that in saline-treated mice (Fig 5A). Notably, the survival time of Doc/MNTX-treated mice was significantly greater than that of Doc-treated mice (Fig 5A). Conversely, the combined use of Doc and OGF was likely to shorten survival relative to that with Doc alone (S7B Fig). There was no difference in survival time between MNTX-treated mice and saline-treated mice (S7C Fig). In accordance with these effects, visceral pain-related hunching behavior on day 35 after inoculation was apparently decreased in Doc/MNTX-treated mice compared with Doc-treated mice (Fig 5B). Importantly, a booster effect of MNTX with respect to Doc was not observed in an OGFR shRNA-transfectant, 60As6-OGFR-KD, in vivo (Fig 5C). The eradication of free tumor cells and suppression of the formation of multiple small tumor nodules on the membranes of the abdomen are major challenges in the treatment of peritoneal metastasis. To clarify the effects of Doc/MNTX in this regard, we monitored 60As6-GFP cells on the membranes of the abdomen. In mice treated with saline, several 1–3 mm tumors studding the mesentery adjacent to the bowel were observed on day 31 after inoculation (Fig 6A). In mice that had been treated with Doc or Doc/MNTX, fewer tumor nodules were noted on day 49 (Fig 6A, white box in the upper region of the cecum). However, isolated tumor cells and small tumor cell spheroids, which were located in the vascular bed of the mesentery, were found only in Doc-treated mice (Fig 6A). Based on the results of microscopic observation, there were significantly fewer single cells and spheroids in Doc/MNTX-treated mice than in Doc-treated mice (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