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Hippocrates’ assertion that ‘what the lance does not heal, fire will’ underscores the fact that for thousands of years heat
has been used to treat a variety of diseases, including cancer. Indeed, spontaneous tumor remission has been observed in patients
following feverish infection [1], and expression of activated oncogenes, such as Ras, can render tumor cells sensitive to
heat compared with normal cells [2, 3]. In the past, a primary drawback to the use of heat as a clinical therapy was the inability
to selectively focus heat to tumors in situ. Of late, however, several approaches have been devised to deliver heat more precisely, including the use of heated nanoparticles,
making hyperthermia a more clinically tractable treatment option [4, 5]. Despite these practical advances, the mechanisms
responsible for heat shock-induced cell death remain controversial and ill-defined. In this Visions and Reflections we discuss recent findings surrounding the initiation of heat shock-induced apoptosis, and propose future areas of research.
Received 17 March 2007; received after revision 25 April 2007; accepted 22 May 2007 相似文献
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Isakovic A Harhaji L Stevanovic D Markovic Z Sumarac-Dumanovic M Starcevic V Micic D Trajkovic V 《Cellular and molecular life sciences : CMLS》2007,64(10):1290-1302
The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density
cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G0/G1 phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction
of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and
oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition
(cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis
(sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C,
an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed
in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic
action of metformin.
Received 14 February 2007; received after revision 26 March 2007; accepted 3 April 2007 相似文献
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Lanzi C Cassinelli G Cuccuru G Zaffaroni N Supino R Vignati S Zanchi C Yamamoto M Zunino F 《Cellular and molecular life sciences : CMLS》2003,60(7):1449-1459
Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic
events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could
thereby represent a specific therapeutic approach. We previously described the inhibitory activity
of the 2-indolinone derivative RPI-1 (formerly Cpd1) on the tyrosine kinase activity and transforming
ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the
present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell
line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell
proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells,
Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase
C, thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation
of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways.
In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly
85%. These findings in a cellular context relevant to the pathological function of RET oncogenes
support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest
RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors
expressing RET oncogenes.Received 31 December 2002; received after revision 21 February 2003; accepted 10 April 2003 相似文献
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