Disease relevance of rottlerin

• Furthermore, the glioma cell line U373, which expresses endogenous PKCdelta, underwent apoptosis in response to etoposide, and the apoptotic response was blocked by the PKCdelta inhibitor rottlerin [1].
• Data suggest that rottlerin affects mitochondrial function independent of PKC delta, thereby sensitizing cells to TRAIL, and that mitochondria constitute an important target in overcoming inherent resistance to TRAIL in colon carcinomas [2].
• The effects of PMA on MAPK phosphorylation and glioblastoma cell proliferation were reduced by BIM, rottlerin, the MEK inhibitor U0126, and PKCdelta and c-Src siRNAs [3].
• We selectively blocked the activity of PKC isoforms by using GF 109203X or rottlerin and demonstrated that this inhibition largely decreased lytic KSHV reactivation by TPA [4].
• METHODS: In this report we compared the effect of staurosporine, Bis II, Gö 6976, rottlerin, and pertussis toxin on histamine release from human basophils mediated by the following stimuli: HrHRF, polyclonal human anti-IgE antibody, and antigen, as well as the IgE-independent stimulus, FMLP [5].

High impact information on rottlerin

• This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter [6].
• In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675 [6].
• Furthermore, the PKCdelta/PKC inhibitor rottlerin prevented the effects induced by phorbol 12-myristate 13-acetate and human neutrophil elastase, suggesting that PKCdelta and PKC are involved in Duox1 activation [7].
• In VASP(-/-) platelets, the enhancement of filopodia generation, actin polymerization, and platelet aggregation by rottlerin is ablated [8].
• Cotreatment with rottlerin, a PKCdelta-specific inhibitor, completely blocks NSC606985-induced mitochondrial DeltaPsim loss and caspase-3 activation, while the inhibition of caspase-3 by z-DEVD-fluoromethyl ketone (Z-DEVD-fmk) only partially attenuates PKCdelta activation and apoptosis [9].

Chemical compound and disease context of rottlerin

• In the present study, we investigated the effects of several selective protein kinase C (PKC) inhibitors (Gö6976, Gö6983, bisindolylmaleimide I, and rottlerin) in combination with conventional anticancer drugs on apoptosis and long-term anchorage-independent growth of both parental and Bcl-2-overexpressing mammary adenocarcinoma MTLn3 cells [10].
• Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells [11].
• Kainate-induced neuronal death was significantly increased by pharmacological inhibition of PKC-delta with rottlerin, suggesting a protective role of PKC-delta against kainate toxicity [12].
• Using the trypan blue exclusion assay, we demonstrated that rottlerin reduced the viability in a dose- and time-dependent manner of human leukemia HL60 cells, human acute T cell leukemia Jurkat cells and mouse macrophage RAW 264.7 cells [13].

Biological context of rottlerin

• Pretreatment of these cells with the PKC-delta inhibitor rottlerin prevented the thrombin-induced phosphorylation of p38 MAP kinase, suggesting that p38 MAP kinase signals downstream of PKC-delta [14].
• Both the PKC delta inhibitor rottlerin and ectopic expression of a dominant negative form of PKC delta independently restored SRE-dependent transcription and immediate-early gene expression in senescent cells [15].
• The biological significance of these findings is implicated by the finding that rottlerin, a selective PKCtheta inhibitor, blocked FasL induction by anti-CD3 or PMA plus ionomycin stimulation and, consequently, protected human Jurkat T cells and the mouse T cell hybridoma A1.1 from activation-induced cell death [16].
• DNA damage-induced SAPK activation was attenuated by (i) treatment with rottlerin, (ii) expression of a kinase-inactive PKCdelta(K-R) mutant, and (iii) down-regulation of PKCdelta by small interfering RNA (siRNA) [17].
• Pretreatment with the PKC delta-selective inhibitor rottlerin or transfection with an antisense PKC delta oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC delta plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC delta in cIAP-2 induction [18].

Anatomical context of rottlerin

• Similar to the situation in splenic B cells, rottlerin inhibits BCR and PMA stimulation of NF-kappaB in 70Z/3 cells [19].
• However, after 15-min incubation with rottlerin, mitochondrial membrane potential (Delta psi m) was dramatically reduced in RKO cells, and, in cells subsequently treated with TRAIL, rapid apoptosis was evident within 8 h [2].
• In contrast, a PKCdelta inhibitor, rottlerin, had an opposite effect on cell clustering and caused dissociation of cell junctions [20].
• Furthermore, lysate-derived PKCdelta from activated monocytes phosphorylated p47phox in a rottlerin-sensitive manner [21].
• Signaling via both the TCR and CD28 is required for optimal activation of the multisubunit IkappaB kinase (IKK) complex in primary human T lymphocytes; this activation could be inhibited by a Ca(2+)-independent PKC isoform inhibitor, rottlerin [22].

Associations of rottlerin with other chemical compounds

• Furthermore, rottlerin blocked combined MGO and cisplatin-induced ROS generation and apoptosis [23].
• Exposure of freshly isolated parotid acinar cells to rottlerin and FCCP reduced cellular ATP levels and reduced stimuli-dependent increases in tyrosine phosphorylation of PKCdelta [24].
• Similarly, calphostin C and rottlerin depressed activation of p44/42 MAPK [25].
• Kinetic studies using the protein synthesis inhibitor cycloheximide showed that TRO, RSG, and rottlerin shortened the half-life of p21(Cip1) protein [26].
• MGO and cisplatin increased PKCdelta activity by 4-fold, and this effect was blocked by the PKCdelta inhibitor rottlerin but not by NAC [23].

Gene context of rottlerin

• Interestingly, both rottlerin and EGF induced substantial increases in phospholipase D (PLD) activity, which is commonly elevated in response to mitogenic stimuli [27].
• Furthermore, rottlerin, an inhibitor of protein kinase Cdelta (PKCdelta) and calmodulin kinase III, abrogated the up-regulation at both protein and mRNA levels [28].
• Expression of a dominant negative PKC delta mutant (PKC delta-KR) or pretreatment of cells with rottlerin, a chemical PKC delta inhibitor, attenuated TNF-alpha- and phorbol ester-induced transcription from the IL-8 promoter [29].
• The inhibition of PKCdelta by rottlerin did not affect the activation of p38 MAPK by arsenate [28].
• The later JNK1 activation and apoptotic progression are also prevented by co-treatments of cells with rottlerin, a PKC-delta inhibitor or z-VAD-fmk, a pan caspase inhibitor [30].

Analytical, diagnostic and therapeutic context of rottlerin

• Stats (signal transducers and activators of transcription) 3 and 5 DNA binding activities were induced by PRL/rPL-1 treatment of luteinized granulosa cells but only Stat 3 DNA binding was reduced by rottlerin [31].
• Immunofluorescence analyses demonstrated fewer stress fibers and focal contacts in rottlerin-treated or Ad PKCdeltadn-infected EC; yet, PKCdelta inhibition caused no significant changes in microtubule structures [32].
• In intracellular perfusion with rottlerin (1 microM) or staurosporine (10 microM), phorbol 12-myristate 13-acetate-induced inhibition of I(K(Ca)) in these cells was abolished [33].
• Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with sorafenib and rottlerin as single agents or in combination [11].
• Titration of [Cl(-)](i) from 20-140 mM in nystatin-permeabilized cell monolayers did not affect the baseline activity of PKC-delta, PKC-zeta, or rottlerin-sensitive NKCC1 [34].

References