▎ PNC 27 Numekuku
Nukae nye PNC-27 ƒe dɔwɔwɔ?
1, Ʋumenugbagbeviɣidɔ dada:
PNC-27 te ŋu blaa HDM-2 protein ɖe kansa lãmenugbagbeviwo ƒe lãkusi dzi eye wònaa lãmenugbagbeviwo ƒe aɖi ƒe ʋuʋudedi siwo to lãkusi me la dzɔna. Le numekuku aɖe si wowɔ le amegbetɔ ƒe non-stem cell acute myeloid leukemia cell lines ŋu me la, wokpɔe be HDM-2 dzena ŋutɔ le U937 (acute monocytic leukemia), OCI-AML3 (acute granulomonocytic leukemia), kple HL60 (acute promyelocytic leukemia) lãmenugbagbeviwo ƒe lãkusiwo me.PNC-27 blana ɖe HDM-2 ŋu le lãkusiwo dzi, eye wòʋãa ame necroptosis kple LDH (lactate dehydrogenase) ƒe dodo le gaƒoƒo 4 me. (LDH) ƒe dodo le gaƒoƒo 4 me. HDM-2 ƒe taɖodzinu ɖoɖo ɖe lãmenugbagbeviwo ƒe lãkusi dzi ate ŋu anye mɔnu si woate ŋu azã atsɔ ada ʋumenugbagbeviɣidɔ.PNC-27 ɖe ʋumenugbagbeviɣidɔ ƒe dɔwɔwɔ ɖedzesi aɖe fia le ʋumenugbagbeviɣidɔ ƒe lãmenugbagbevi geɖe me to ŋkuléle ɖe Membrane HDM-2 ŋu me [1]..
2. Enaa tumor cell lysis
Ewɔa dɔ abe peptide si me gblẽ o ene:
Numekuku geɖe ɖee fia be PNC-27 nana tumor cell lysis abe peptide si me gblẽ o ene tsɔ wu be wòanye kakɛ aɖe. Le kpɔɖeŋu me. Nusiwo do tso eme ɖee fia be punctate yellow fluorescence si to vovo le kansa lãmenugbagbeviwo ƒe lãkusi dzi le miniti 30 me, si ɖee fia be peptide si me gblẽ o la nɔ kansa lãmenugbagbeviwo ƒe lãkusi dzi eye wòdzi ɖe edzi kple kansa lãmenugbagbeviwo ƒe ʋuʋu. To vovo na ema la, MCF-10-2A lãmenugbagbevi siwo wometrɔ o ɖe lãkusi ɣi ƒe keklẽ si sɔ fia le gɔmedzedzea me, gake emegbe wobu. To vovo na kansa lãmenugbagbeviwo la, lãmenugbagbevi siawo siwo metrɔ o la gakpɔtɔ nɔ agbe. Esia fia be PNC-27 nana lãkusiwo me mãna le kansa lãmenugbagbeviwo me to dɔwɔwɔ abe peptide blibo ene, ke menye abe kakɛ aɖe ene o [2]..
Babla ɖe HDM-2 ŋu be wòawɔ ʋuʋudedi ƒe wɔwɔmewo:
HDM-2-binding structural domain kple cell-penetrating peptide (CPP) presequence le PNC-27 me, si nana pore structures ƒe wɔwɔ to kadodo kple HDM-2 le cell membrane dzi, si hea tumor cell lysis kple necrosis vɛ. Conformational energy akɔntabubuwo ɖee fia be PNC-27 wɔa complex kple HDM-2 le 1:1 ƒe sɔsɔme me, eye ŋgɔdola ƒe ɖoɖo si fia asi adzɔge tso complex la gbɔ. Dɔlélenutsiŋutete ƒe elektrɔnik nusuekpɔmɔ̃ ŋuti numekukuwo ɖee fia be sika ƒe akpa vovovo siwo woŋlɔ ɖe 6 nm kple 15 nm ƒe anyinɔnɔ le xexlẽme si ade 1:1 me le ʋuʋudedi siwo le kansa lãmenugbagbevi siwo wotsɔ PNC-27 da dɔe ƒe anyime, si fia be nu vovovo siawo le vevie na ʋuʋudedi ƒe wɔwɔme. To vovo na ema la, womewɔ ʋuʋudedi aɖeke le fibroblasts siwo dzi woɖu, siwo wometrɔ o siwo wotsɔ PNC-27 da dɔe me o [3]..
Dɔdzẽ si le dɔgboa me:
PNC-27 peptide yeye si tsia kansa nu la naa amegbetɔ ƒe dɔgbo me MiaPaCa-2 kansa lãmenugbagbeviwo ƒe kuku le mɔ si nɔa te ɖe agbɔsɔsɔme si wozã dzi, gake menye aɖi na lãmenugbagbevi siwo sɔ o. Numekukuwo ɖee fia be ne wotsɔ PNC-27 kpe ɖe Gemzar, si nye atike si wozãna tsɔ daa dɔdzẽ si le dɔgboa me ŋu la, ekpɔa ŋusẽ ɖe MiaPaCa-2 lãmenugbagbeviwo dzi wu Gemzar alo PNC-27 ɖeɖeko. Esia ate ŋu atso esi PNC-27 ƒe ʋuʋudediwo dzia kansa lãmenugbagbeviwo ƒe gege ɖe Gemzar me ɖe edzi, si wɔnɛ be Gemzar geɖe wu te ŋu tɔa ŋku kansa lãmenugbagbeviwo [1] ..
Azigolo me Kansa:
Le azigolo me kansa lãmenugbagbeviwo ƒe hatsotso SKOV-3 kple OVCAR-3 me la, HDM-2 protein dzena ŋutɔ le lãmenugbagbeviwo ƒe lãkusi me.PNC-27 nɔa teƒe ɖeka kple HDM-2 le lãmenugbagbeviwo ƒe lãkusi me, si hea lãmenugbagbeviwo ƒe kuku kabakaba vɛ. To vovo na esia la, le lãmenugbagbevi siwo wometrɔ o si wotsɔ ɖua lãmenugbagbevi siwo dzi woɖuna ƒe hatsotso si nye HUVEC me la, womekpɔ PNC-27 ƒe teƒe ɖeka nɔnɔ kple aɖi si le lãmenugbagbeviwo me o le esi membrane HDM-2 ƒe ɖeɖefia suetɔ kekeake ta [1]..
Dɔgbome Kansa:
PNC-27 tiaa dɔgbo me dɔdzẽ ƒe lãmenugbagbeviwo. Le dɔgbo me kansa lãmenugbagbeviwo ƒe hatsotso ade me la, PNC-27 nɔa teƒe ɖeka kple membrane HDM-2 eye wòna lãmenugbagbeviwo ku (tumor cell necrosis, LDH ƒe dodo fũ, membrane associated protein V kple cysteine 3 negativity) le kansa lãmenugbagbeviwo me ko. Le vivo me la, PNC-27 nana tumor nodules ƒe necrosis gake mekpɔa ŋusẽ ɖe lãmeka siwo sɔ dzi o [1]..
3. Dɔlékuiwutikewo ƒe dɔwɔwɔ nyuie wu
Doxil ƒe babla:
Wokpɔe be PNC27 peptide, abe ligand si woɖo taɖodzinu na ene, ate ŋu ana Doxil ƒe dɔwɔwɔ ɖe dɔdzẽ nu le kansa lãmenugbagbevi siwo me HDM2 le me nadzi ɖe edzi ŋutɔ. Wotsɔ PNC27 peptide ƒe agbɔsɔsɔ vovovowo de Doxil me, eye wowɔ flow cytometry kple confocal analysis le C26 dɔgbo me kansa (HDM2-positive) kple B16F0 melanoma (HDM2-negative) lãmenugbagbeviwo ŋu. Nusiwo do tso eme ɖee fia be PNC27-Doxil ɖe lãmenugbagbeviwo ƒe xɔxlɔ̃ kple lãmenugbagbeviwo ƒe aɖiwɔwɔ ɖedzesi fia le C26 lãmenugbagbeviwo me, evɔ womekpɔ emetsonu siawo le B16F0 lãmenugbagbeviwo me o. Le kpɔɖeŋu me, PNC27-Doxil (100 PNC27 peptide) dzi Doxil ƒe atikewɔwɔ ƒe ŋutete ɖe edzi ŋutɔ evɔ mekpɔ ŋusẽ ɖe eƒe nugbagbewo ƒe mama dzi le C26 dɔdzẽwo me o [4]..
4. Azigolo me dɔdzẽ dada ɖekae kple paclitaxel
Wozãa paclitaxel geɖe le nyɔnuwo ƒe dɔléle vɔ̃ɖiwo dada me, gake eɖoa taɖodzinu na dɔdzẽ ƒe lãmenugbagbevi siwo le lãmenugbagbeviwo ƒe tsatsam ƒe akpa si nye M, eye lãmenugbagbevi siwo le akpa bubuwo me nɔa agbe eye ate ŋu ana dɔdzẽa nagagbugbɔ.PNC-27 nye peptide si wowɔ tso amino acidwo me le P53-MDM-2 binding domain me si wua kansa lãmenugbagbeviwo ƒe hatsotso vovovowo le mɔ si nɔa te ɖe agbɔsɔsɔme si wozã dzi. Wokpɔe be azigolo me dɔdzẽ ID8 lãmenugbagbevi siwo wotsɔ paclitaxel do goe la ɖea MDM-2 ƒe ɖeɖefia dzi ɖe edzi eye woƒe seselelãme dzi ɖe edzi ɖe PNC-27 ŋu.PNC-27 ƒe lãmenugbagbeviwo ƒe aɖi ƒe ŋusẽkpɔɖeamedzi nɔ te ɖe eƒe kadodo kple MDM-2 dzi, eye mɔxexe ɖe MDM-2 nu xea mɔ na PNC-27 ƒe amewuwu ƒe ŋusẽkpɔɖeamedzi. Heterodrug nɔnɔmetata siwo le agbɔsɔsɔme ƒokpliawo me la wɔ ɖeka, si fia be dɔwɔwɔ aduadu ƒe ŋusẽkpɔɖeamedzi le PNC-27 kple paclitaxel dome [5] . Le azigolo me dɔdzẽ (ID8) ƒe kpɔɖeŋu aɖe si wowɔ le dɔgboa me me la, PNC-27 tsɔtsɔ kpe ɖe paclitaxel dodo kwasiɖa sia kwasiɖa ŋu ɖe dɔdzẽ ƒe tsitsi dzi kpɔtɔ ŋutɔ. Nyatakaka siawo ɖee fia be PNC-27 kple paclitaxel wɔa dɔ aduadu, eye PNC-27 tɔa ŋku paclitaxel si tsi agbe le lãmenugbagbeviwo me eye wòna eƒe dɔlékuiwutikewo ƒe ŋusẽkpɔɖeamedziwo nyona ɖe edzi.
5. Azigolo me kansa gbãtɔ si le lãkusi me la dada
Numekuku aɖe ɖo dekɔnu gbãtɔ siwo me woɖe azigolo me dɔdzẽ ƒe lãmenugbagbevi siwo woɖe ɖe vovo yeyee tso dɔnɔ siwo ŋu wokpɔ azigolo me cystadenocarcinoma le yeyee gbɔ. Wo dometɔ ɖeka tso mucinous cystadenocarcinoma me eye evelia tso high-grade papillary plasmacytoid carcinoma me. Woda PNC-27 ƒe atikewɔwɔ ƒe ŋutete kpɔ le agbɔsɔsɔ me to kekeli ƒe nusuekpɔmɔ̃ ƒe ŋkuléle ɖe eŋu kple MTT lãmenugbagbeviwo ƒe dzidziɖedzi dodokpɔ kpakple lactate dehydrogenase (LDH) dzidzedze me. Nusiwo do tso eme ɖee fia be PNC-27 xe mɔ na amegbetɔ ƒe kansa lãmenugbagbevi gbãtɔ siwo woɖe ɖe vovo yeyee tso azigolo me dɔdzẽ eve me ƒe tsitsi le mɔ si nɔ te ɖe agbɔsɔsɔme si wozã dzi eye wònye lãmenugbagbeviwo ƒe aɖi na wo. Peptide si woyɔna be control peptide PNC-29 mekpɔ ŋusẽ aɖeke ɖe kansa lãmenugbagbevi gbãtɔwo dzi o. Tsɔ kpe ɖe eŋu la, PNC-27 hã nye lãmenugbagbeviwo ƒe aɖi na amegbetɔ ƒe azigolo me dɔdzẽ ƒe lãmenugbagbevi siwo li ɣeyiɣi didi aɖe eye wote ŋu nɔa te ɖe atikewɔmɔnu nu [6] ..
Kpuie ko la, PNC-27, abe kansadɔlékuiwutike yeye ene, ɖe ŋutete gã aɖe fia be woate ŋu azãe le kansadɔdamɔnu vovovowo me. Le ʋumenugbagbeviɣidɔ gome la, PNC-27 ɖe amewuwu ƒe ŋusẽkpɔɖeamedzi tiatia fia ɖe ʋumenugbagbeviɣidɔ sesẽ (le kpɔɖeŋu me, U937, OCI-AML3, kple HL60 lãmenugbagbevi ƒomeviwo) kple K562 lãmenugbagbevi siwo me p53 mele o dzi, eye wòkpɔ dɔlékuiwutike ƒe ŋusẽkpɔɖeamedzi siwo wɔa dɔ nyuie ŋutɔ to lãmenugbagbeviwo ƒe kuku kple lactate dehydrogenase ƒe dodo me. Le azigolo me dɔdzẽ dada me la, PNC-27 kple paclitaxel ƒe ƒuƒoƒo ɖe dɔwɔwɔ aduadu fia, si ate ŋu axe mɔ ɖe dɔdzẽ ƒe tsitsi nu vevie eye wòagawu lãmenugbagbevi siwo te ŋu nɔa te ɖe atikewɔmɔnu nu la nu. Tsɔ kpe ɖe eŋu la, PNC-27 ƒe ƒoƒo ƒu kple liposomal atikewo (le kpɔɖeŋu me, Doxil) abe ligand si woɖo taɖodzinu na ene ate ŋu ana atike la ƒe dɔwɔwɔ tɔxɛ kple esi tsi tre ɖe dɔdzẽ ŋu nadzi ɖe edzi na HDM2-positive tumor cells. Eƒe mɔxexeɖedɔléle nu ƒe ŋusẽkpɔɖeamedzi ɖe azigolo me kansa gbãtɔ ƒe lãmenugbagbeviwo dzi gaɖo kpe dɔdamɔnu ƒe gɔmeɖeɖe ƒe asixɔxɔ dzi. Fifia la, PNC-27 ge ɖe afɔɖeɖe I ƒe dɔdamɔnu dodokpɔwo me, eye ehiã be woawɔ dɔdamɔnu ŋuti numekuku geɖe wu be woatsɔ aɖo kpe eƒe dedienɔnɔ kple eƒe dɔwɔwɔ ɣeyiɣi didi dzi, ale be woadoe ɖe ŋgɔ be wòanye egbɔkpɔnu yeye aɖe na kansa dada.
Le Agbalẽŋlɔla La Ŋu
Nusiwo míeyɔ ɖe etame la katã nye esiwo ŋu Cocer Peptides wɔ numekuku le, trɔ asi le wo ŋu eye woƒo wo nu ƒu.
Dzɔdzɔmeŋutinunya ƒe Agbalẽŋlɔla
Sarafraz-Yazdi E nye numekula si do ƒome kple habɔbɔ geɖe, siwo dometɔ aɖewoe nye NomoCan, New York Ʋu Dɔwɔƒe, SUNY Downstate Lãmesẽŋutinunya Yunivɛsiti, kple New York Harbor VA Med Ctr. Habɔbɔ siawo te gbe ɖe eƒe gomekpɔkpɔ le numekuku kple atikewɔwɔ ƒe nɔnɔme vovovowo me dzi.
Eƒe numekuku ƒe didiwo keke ta le nusɔsrɔ̃ vovovowo abe Dɔdzẽŋutinunya, Atikewɔwɔ Ŋuti Nudokpɔƒe Mɔ̃ɖaŋununya, Atikeŋutinunya & Atikewɔwɔ, Nu gbagbewo ƒe Dzɔdzɔmeŋusẽŋununya & Molecular Biology, kple Numekuku & Dodokpɔ ƒe Atikewɔwɔ me. Dɔ si wòwɔ le go siawo me ɖe eƒe nunya geɖe kple ɖokuitsɔtsɔna be yeado sidzedze ɖe ŋgɔ le atikewɔwɔ ŋuti dzɔdzɔmeŋutinunya kple numekuku ƒe akpa vevi siawo me fia. woŋlɔe ɖe nyayɔyɔ ƒe numekugbalẽ [3] me.
