PPAR-γ activation attenuates deltamethrin-induced apoptosis by regulating cytosolic PINK1 and inhibiting mitochondrial dysfunction.

Central events in the mitochondrial-dependent cell death pathway include the disruption of mitochondrial membrane potential, which causes the release of apoptogenic molecules leading to cell death. Based on the cytotoxic mechanism of deltamethrin (DLM), we examined the neuroprotective mechanisms of rosiglitazone (RGZ), which is against DLM-induced neuronal cell death. In this study, we found that DLM induces apoptosis in SH-SY5Y cells as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, neuronal cell death in response to DLM was due to mitochondrial dependent-apoptosis pathways since DLM increased cytochrome c release into the cytosol and activated caspase-9. DLM exposure reduced PINK1 expression, and pretreatment with RGZ significantly reduced cytochrome c release and caspase-9 activation. RGZ also attenuated the reduction of complex I activity, mitochondrial membrane potential, and ATP levels. Pretreatment with RGZ significantly enhanced PINK1 expression in DLM-exposed cells. In addition, RGZ increased cytosolic PINK1 by inhibiting mitochondrial translocation of PINK1. Interestingly, RGZ fails to rescue DLM-induced mitochondrial dysfunction both in PINK1 knockdown and PPAR-γ antagonist treated cells. Results from this study suggest that RGZ exerts anti-apoptotic effects against DLM-induced cytotoxicity by attenuation of mitochondrial dysfunction through cytosolic PINK1-dependent signaling pathways.

Synergistic, cytotoxic and apoptotic activities of olmesartan with NF-κB inhibitor against HeLa human cell line.

CONTEXT: Over expression of renin-angiotensin system (RAS) and nuclear factor-kappaB (NF-κB) has a major role in many cancers. It has been suggested that some angiotensin receptor blockers (ARBs) could reduce the proliferation of cancer cells. The role of NF-κB pathway has been documented in cell proliferation. OBJECTIVE: In this study, the role of angiotensin II and NF-κB pathway in human cervical cancer cell line (HeLa) proliferation was studied using olmesartan (as a novel Ag II antagonist) and Bay11-7082 (as NF-κB inhibitor). MATERIALS AND METHODS: HeLa cells were treated with different concentrations of olmesartan and Bay11-7082. Cell proliferation was determined after 24, 48, and 72 h by MTT assay. Synergistic activity of olmesartan with Bay11-7082 was analyzed with Compusyn software. Apoptotic cells were determined using PI staining of DNA fragmentation. RESULTS: Cell viability decreased with olmesartan and Bay11-7082 in HeLa cells by 24, 48 and 72 h. Olmesartan had synergistic activity with Bay11-7082 and combinations of olmesartan with Bay11-7082 decreased cell viability as compared with single agent treatments. Olmesartan and Bay11-7082 induced a sub-G1 peak in flow cytometry histogram of treated cells indicating that apoptotic cell death is involved in olmesartan and Bay11-7082-induced toxicity. DISCUSSION AND CONCLUSION: Results imply that olmesartan and Bay11-7082 inhibit the growth of HeLa cells as a concentration- and time-dependent mode and they have synergistic activity. Results show that RAS and NF-κB pathway blockade lead to significant cytotoxicity against tumor cell line. So, ARBs and NF-κB pathway inhibitors could be considered as good anti-cancer agents in cervix carcinoma after further studies.

Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells.

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.

Potentiation of ICI182,780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790.

ICI182,780 (Fulvestrant) is a pure anti-estrogen used in adjuvant therapies of breast cancer. This compound not only inhibits the transcriptional activities of the estrogen receptor-alpha (ER alpha) but also induces its proteasome-dependent degradation. The latter activity is believed to be required for the antiproliferative effects of ICI182,780. Estrogen receptor-related receptor-alpha (ERR alpha) is an orphan member of the nuclear receptor superfamily that is expressed in a wide range of tissues including breast tumors, in which its high expression correlates with poor prognosis. Although not regulated by any natural ligand, ERR alpha can be deactivated by the synthetic molecule XCT790. Here we demonstrate that this compound also induces a proteasome degradation of ERR alpha. We also show that although it does not act directly on the steady-state level of ER alpha, XCT790 potentiates the ICI182,780-induced ER alpha degradation. We suggest that treatment with XCT790 could thus enhance the efficacy of ICI182,780 in ER alpha-dependent pathologies such as breast cancer.

MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.

Interactions between MEK1/2 inhibitors and the dual Abl/Src kinase inhibitor dasatinib (BMS-354825) were examined in chronic myeloid leukemia (CML) cell lines and primary specimens. Cotreatment of K562 or LAMA cells with subtoxic or marginally toxic concentrations of PD184352 (or U0126) and dasatinib synergistically potentiated mitochondrial damage, caspase activation, and apoptosis. Similar interactions were observed in CD34(+) cells from one CML patient-derived but not in a normal human CD34(+) bone marrow cell specimen. These interactions were associated with multiple perturbations in survival signaling pathways, including inactivation of Bcr/Abl, STAT5, and ERK1/2; down-regulation of Bcl-x(L) and Mcl-1; and dephosphorylation/activation of Bim. They were also associated with BAX/BAK conformational change, mitochondrial dysfunction, and caspase activation. Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib/PD184352 lethality. Conversely, K562 cells ectopically expressing Mcl-1 or Bcl-x(L) were significantly less susceptible to dasatinib/PD184352 toxicity. Notably, the dasatinib/PD184352 regimen was active against leukemic cells exhibiting various forms of imatinib mesylate resistance, including Bcr/Abl overexpression, Lyn activation, and several Bcr/Abl kinase domain mutations (eg, E255K, M351T), but not T315I. Together, these findings suggest that strategies combining dasatanib with MEK1/2 inhibitors warrant further investigation in Bcr/Abl(+) malignancies, particularly in the setting of imatinib mesylate-resistant disease.