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Development of pro-apoptotic peptides as potential therapy for peritoneal endometriosis.

Sugihara K, Kobayashi Y, Suzuki A, Tamura N, Motamedchaboki K, Huang CT, Akama TO, Pecotte J, Frost P, Bauer C, Jimenez JB, Nakayama J, Aoki D, Fukuda MN - Nat Commun (2014)

Bottom Line: Endometriosis is a common gynaecological disease associated with pelvic pain and infertility.Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display.When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.

ABSTRACT
Endometriosis is a common gynaecological disease associated with pelvic pain and infertility. Current treatments include oral contraceptives combined with nonsteroidal anti-inflammatory drugs or surgery to remove lesions, all of which provide a temporary but not complete cure. Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display. As most endometriosis occurs on organ surfaces facing the peritoneum, we subtracted a phage display library with female mouse peritoneum tissue and selected phage clones by binding to human endometrial epithelial cells. Proteomics analysis revealed the z13 receptor as the cyclic nucleotide-gated channel β3, a sorting pathway protein. We then linked z13 with an apoptosis-inducing peptide and with an endosome-escaping peptide. When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs. Thus, this study presents a strategy that could be useful to treat peritoneal endometriosis in humans.

No MeSH data available.


Related in: MedlinePlus

Induction of apoptosis in baboon endometriosis tissue in vivo.(a) Quantitative TUNEL analysis. Shown is the percentage of TUNEL-positive endometrial glands in tissues from three control untreated baboons compared with three animals treated with a mixture of dKLAK-z13 and HLAH-z13 peptides (see Methods). The number of glands counted and the number of TUNEL-positive glands (indicated in parentheses) were 5 (0), 8 (0) and 18 (0) for untreated and 8 (1), 18 (2) and 26 (3) for treated. Percentages of TUNEL-positive glands from untreated and treated animals were 0.00%±0.00 (n=3) and 13.53%±1.56 (n=3), respectively. (b) TUNEL assay of baboon endometriosis. Upper panels: hematoxylin and eosin-stained images. Lower panels: TUNEL assay of corresponding areas. Left: an endometrial gland in the ovary. Scale bar, 100 μm. Right: TUNEL-positive cell debris in an endometrial gland in the omentum. Scale bar, 200 μm.
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f6: Induction of apoptosis in baboon endometriosis tissue in vivo.(a) Quantitative TUNEL analysis. Shown is the percentage of TUNEL-positive endometrial glands in tissues from three control untreated baboons compared with three animals treated with a mixture of dKLAK-z13 and HLAH-z13 peptides (see Methods). The number of glands counted and the number of TUNEL-positive glands (indicated in parentheses) were 5 (0), 8 (0) and 18 (0) for untreated and 8 (1), 18 (2) and 26 (3) for treated. Percentages of TUNEL-positive glands from untreated and treated animals were 0.00%±0.00 (n=3) and 13.53%±1.56 (n=3), respectively. (b) TUNEL assay of baboon endometriosis. Upper panels: hematoxylin and eosin-stained images. Lower panels: TUNEL assay of corresponding areas. Left: an endometrial gland in the ovary. Scale bar, 100 μm. Right: TUNEL-positive cell debris in an endometrial gland in the omentum. Scale bar, 200 μm.

Mentions: Histology of hematoxylin and eosin-stained tissue sections revealed evidence of endometriosis in all three animals treated with a mixture of dKLAK-z13 and HLAH-z13 peptides. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays of endometriosis lesions collected from three untreated control baboons revealed no TUNEL positivity in gland tissue (Fig. 6a, left column). By contrast, we found TUNEL-positive glands in tissues collected from all three baboons treated with the dKLAK-z13 and HLAH-z13 peptide mixture (Fig. 6a, right column). Those signals were seen in glandular epithelial cells in ovarian endometriosis and in the lumen of endometrial gland in the omentum (Fig. 6b). No evidence of apoptosis was detected in cells facing peritoneum in liver, kidney, spleen, colon and stomach (data not shown). These results show overall, as proof of concept, that z13-targeted induced apoptosis occurred in endometriosis model in baboons in vivo.


Development of pro-apoptotic peptides as potential therapy for peritoneal endometriosis.

Sugihara K, Kobayashi Y, Suzuki A, Tamura N, Motamedchaboki K, Huang CT, Akama TO, Pecotte J, Frost P, Bauer C, Jimenez JB, Nakayama J, Aoki D, Fukuda MN - Nat Commun (2014)

Induction of apoptosis in baboon endometriosis tissue in vivo.(a) Quantitative TUNEL analysis. Shown is the percentage of TUNEL-positive endometrial glands in tissues from three control untreated baboons compared with three animals treated with a mixture of dKLAK-z13 and HLAH-z13 peptides (see Methods). The number of glands counted and the number of TUNEL-positive glands (indicated in parentheses) were 5 (0), 8 (0) and 18 (0) for untreated and 8 (1), 18 (2) and 26 (3) for treated. Percentages of TUNEL-positive glands from untreated and treated animals were 0.00%±0.00 (n=3) and 13.53%±1.56 (n=3), respectively. (b) TUNEL assay of baboon endometriosis. Upper panels: hematoxylin and eosin-stained images. Lower panels: TUNEL assay of corresponding areas. Left: an endometrial gland in the ovary. Scale bar, 100 μm. Right: TUNEL-positive cell debris in an endometrial gland in the omentum. Scale bar, 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109024&req=5

f6: Induction of apoptosis in baboon endometriosis tissue in vivo.(a) Quantitative TUNEL analysis. Shown is the percentage of TUNEL-positive endometrial glands in tissues from three control untreated baboons compared with three animals treated with a mixture of dKLAK-z13 and HLAH-z13 peptides (see Methods). The number of glands counted and the number of TUNEL-positive glands (indicated in parentheses) were 5 (0), 8 (0) and 18 (0) for untreated and 8 (1), 18 (2) and 26 (3) for treated. Percentages of TUNEL-positive glands from untreated and treated animals were 0.00%±0.00 (n=3) and 13.53%±1.56 (n=3), respectively. (b) TUNEL assay of baboon endometriosis. Upper panels: hematoxylin and eosin-stained images. Lower panels: TUNEL assay of corresponding areas. Left: an endometrial gland in the ovary. Scale bar, 100 μm. Right: TUNEL-positive cell debris in an endometrial gland in the omentum. Scale bar, 200 μm.
Mentions: Histology of hematoxylin and eosin-stained tissue sections revealed evidence of endometriosis in all three animals treated with a mixture of dKLAK-z13 and HLAH-z13 peptides. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays of endometriosis lesions collected from three untreated control baboons revealed no TUNEL positivity in gland tissue (Fig. 6a, left column). By contrast, we found TUNEL-positive glands in tissues collected from all three baboons treated with the dKLAK-z13 and HLAH-z13 peptide mixture (Fig. 6a, right column). Those signals were seen in glandular epithelial cells in ovarian endometriosis and in the lumen of endometrial gland in the omentum (Fig. 6b). No evidence of apoptosis was detected in cells facing peritoneum in liver, kidney, spleen, colon and stomach (data not shown). These results show overall, as proof of concept, that z13-targeted induced apoptosis occurred in endometriosis model in baboons in vivo.

Bottom Line: Endometriosis is a common gynaecological disease associated with pelvic pain and infertility.Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display.When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.

ABSTRACT
Endometriosis is a common gynaecological disease associated with pelvic pain and infertility. Current treatments include oral contraceptives combined with nonsteroidal anti-inflammatory drugs or surgery to remove lesions, all of which provide a temporary but not complete cure. Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display. As most endometriosis occurs on organ surfaces facing the peritoneum, we subtracted a phage display library with female mouse peritoneum tissue and selected phage clones by binding to human endometrial epithelial cells. Proteomics analysis revealed the z13 receptor as the cyclic nucleotide-gated channel β3, a sorting pathway protein. We then linked z13 with an apoptosis-inducing peptide and with an endosome-escaping peptide. When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs. Thus, this study presents a strategy that could be useful to treat peritoneal endometriosis in humans.

No MeSH data available.


Related in: MedlinePlus