BJC：可诱导正常细胞抑制癌细胞生长

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英国一项最新研究发现，一种特殊的“激酶抑制剂”可以帮助健康细胞和癌细胞进行“对话”，最终“说服”癌细胞回到正常细胞状态。/ r' C/ F0 i1 ?: Q( U  p
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来自英国曼彻斯特大学和索尔福德大学的研究人员在新一期《英国癌症杂志》上报告说，他们在试管中混合培养健康细胞和癌细胞，当加入这种“激酶抑制剂”后，健康细胞和癌细胞的表面建立起了信息传递通道，随后健康细胞似乎“控制”了癌细胞的生长，癌细胞最终停止无序繁殖扩散，其行为变得和正常细胞一样。
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; x0 e* P3 Z3 P: v' S一般情况下，人体中各种细胞都有序地生长、繁殖和死亡，但发生病变的癌细胞常常会失去控制地进行分化和繁殖。
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" {" I) S" U1 Y9 X/ {$ P研究人员说，即使在移除这种“激酶抑制剂”后，健康细胞和癌细胞间已建立的交流通道仍然会保持通畅。再加上这种“激酶抑制剂”没有毒性，今后可以在此基础上开发出快捷高效并且副作用小的癌症疗法。
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/ Q" z6 P' q$ y* J* R/ ~不过，研究也显示，如果向只含有癌细胞的试管中加入这种物质，则基本没有效果。这说明需要有大量的健康细胞来进行“说服”癌细胞的工作。
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7 y% l5 v; {* x- @就一般情况下人体中健康细胞和癌细胞的比例而言，这种物质可以起到良好的治疗效果。
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原始出处：* h: [5 Z8 ^0 x% K
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British Journal of Cancer (2009) 101, 829–839. doi:10.1038/sj.bjc.6605208- f& T& ?* g& }( o+ v% U
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Analogues of Y27632 increase gap junction communication and suppress the formation of transformed NIH3T3 colonies- Y+ n& o0 U5 }
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L Hampson1, X T He1, A W Oliver1, J A Hadfield2, T Kemp2, J Butler2, A McGown2, H C Kitchener1 and I N Hampson1
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1University of Manchester School of Cancer Studies and Imaging Science, Gynaecological Oncology Laboratories, St Mary's Hospital, Hathersage Road, Manchester M13 OJH, UK
; E" d8 k: F- M7 ~9 \, q2Centre for Molecular Drug Design, Kidscan Laboratories, Cockcroft Building, University of Salford, Manchester M5 4WT, UK
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5 i5 o6 W5 i# K1 cbackground:  Constitutive activation of RhoA-dependent RhoA kinase (ROCK) signalling is known to promote cellular transformation and the ROCK inhibitor Y-27632 has the ability to suppress focus formation of RhoA transformed NIH3T3 cells.. e! O, P4 ~2 {

' U- s  T7 ?; D/ V: @methods:  Sixty-four novel structural analogues of Y27632 were synthesised and tested for their ability to persistently inhibit the transformation of NIH3T3 cells by Rho guanidine exchange factor 16 (ARHGEF16) or Ras. In vitro kinase inhibitor profiling, co-culture of transformed cells with non-transformed cells and a novel Lucifer yellow/PKH67 dye transfer method were used to investigate their mode of action.' ~2 @7 Q* S! G, e; w5 _, ?

! a* O! n) z) m3 l4 tresults:  Four Y27632 analogues inhibited transformed focus formation that persisted when the compound was withdrawn. No toxicity was observed against either transformed or non-transformed cells and the effect was dependent on co-culture of these two cell types. In vitro kinase inhibitor profiling indicated that these compounds had reduced activity against ROCK compared with Y27632, targeting instead Aurora A (AURKA), p38 (MAPK14) and Hgk (MAP4K4). Dye transfer analysis showed they increased gap junction intercellular communication (GJIC) between transformed and non-transformed cells.7 l. H$ d$ o1 L' Y" L

& o! |7 v2 O2 n$ Uconclusions:  These data are the first to suggest that transient blockade of specific kinases can induce a persistent inhibition of non-contact inhibited transformed colony formation and can also remove pre-formed colonies. These effects could potentially be mediated by the observed increase in GJIC between transformed and non-transformed cells. Selection of kinase inhibitors with this property may thus provide a novel strategy for cancer chemoprevention.