17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and Colorectal-Neoplasms

To explore the effect of heat shock protein 90 (HSP90) inhibitor (17-DMAG) and oxaliplatin on the proliferation and invasion of colorectal cancer.. After 17-DMAG, oxaliplatin and half-dose combination of 2 drugs processing colorectal cancer SW480 and HCT116 cell lines, CCK8 assay was applied to detect cell viability. RT-PCR and Western blot were used to detect the expression level of the apoptosis-related molecules. Transwell chemokine axis experiment and Western blot were employed to detect cell invasion ability and the expression level of tumor metastasis-associated protein.. The growth of SW480 and HCT116 cells was inhibited after the administration of 17-DMAG and oxaliplatin(P<0.05) in dose- and time-dependent manner. Processed by 17-DMAG 100 nmol/L, oxaliplatin 50 mg/L and half-dose combination of 2 drugs, transcription level of the apoptosis inhibitory gene (Bcl-2) in SW480 and HCT116 cells was decreased, the level of apoptosis promoting gene (Bax) transcription and protein PARP-1 spliceosome expression was increased, and the above trend was more obvious when using half-dose combination of 2 drugs. Transwell chemokine axis experiments showed the penetrating relative percentage and expression level of MMP9 and integrin β3 decreased, especially for half-dose combination of 2 drugs.. 17-DMAG and oxaliplatin can co-inhibit the proliferation and invasion of colorectal cancer.

Topics: Antineoplastic Agents; Apoptosis; Benzoquinones; Cell Proliferation; Cell Survival; Colorectal Neoplasms; HCT116 Cells; Humans; Lactams, Macrocyclic; Neoplasm Invasiveness; Organoplatinum Compounds; Oxaliplatin

Hsp90 is widely overexpressed in cancer cells and believed to be essential for the maintenance of malignant phenotypes. Targeting Hsp90 by small molecules has shown promise in solid and hematologic malignancies, which likely involves degradation of client oncoproteins in a cell-type-specific manner. In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53-dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells. Deficiency in PUMA, BAX, or p53, at lesser extent, abrogated 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced apoptosis and mitochondrial dysfunction, and enhanced clonogenic cell survival. Furthermore, suppression of p53-dependent p21 induction or enhanced p53 activation synergized with 17-AAG to induce PUMA-dependent apoptosis. Finally, PUMA was found to mediate apoptotic and therapeutic responses to the 17-AAG analog 17-DMAG in xenografts. These results show an important role of the p53/PUMA/Bax axis in Hsp90 inhibitor-induced killing of p53 wild-type cells, and have important implications for their clinical applications.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Benzoquinones; Cell Line, Tumor; Colorectal Neoplasms; DNA Damage; HCT116 Cells; HSP90 Heat-Shock Proteins; Humans; Isoxazoles; Lactams, Macrocyclic; Mice; Mice, Nude; Mitochondria; Proto-Oncogene Proteins; Resorcinols; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Ischemia/reperfusion (I/R) is often inevitable during hepatic surgery and may stimulate the outgrowth of colorectal micrometastases. Postischemic microcirculatory disturbances contribute to I/R damage and may induce prolonged tissue hypoxia and consequent stabilization of hypoxia-inducible factor (HIF)-1alpha. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1alpha to I/R-accelerated tumor growth. Partial hepatic I/R attributable to temporary clamping of the left liver lobe induced microcirculatory failure for up to 5 days. This was accompanied by profound and prolonged perinecrotic tissue hypoxia, stabilization of HIF-1alpha, and massive perinecrotic outgrowth of pre-established micrometastases. Restoration of the microcirculation by treatment with Atrasentan and L-arginine minimized hypoxia and HIF-1alpha stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1alpha by the HSP90 inhibitor 17-DMAG caused an increase in tissue necrosis but reduced I/R-stimulated tumor growth by more than 70%. In conclusion, prevention of postischemic microcirculatory disturbances and perinecrotic hypoxia reduces the accelerated outgrowth of colorectal liver metastases after I/R. This may, at least in part, be attributed to the prevention of HIF-1alpha stabilization. Prevention of tissue hypoxia or inhibition of HIF-1alpha may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery.

Topics: Animals; Arginine; Atrasentan; Benzoquinones; Cell Line, Tumor; Colorectal Neoplasms; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Lactams, Macrocyclic; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Microcirculation; Necrosis; Neoplasm Transplantation; Pyrrolidines; Reperfusion Injury; Time Factors; Tumor Burden