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[]
["TTD - Therapeutic Targets Database"]
["Version 4.3.02 (2011.08.25)"]
["File Name: Pharmacodynamically synergistic drug combinations due to anti-counteractive actions."]
["Synergy has been determined by well established synergy/additive analysis methods and its molecular mechanism has been revealed."]
[]
["Combination target relationship","Drug A (mechanism of actions related to synergy)","Drug B (mechanism of actions related to synergy )","Reported synergistic effect ","Synergism determination method","Possible mechanism of synergism in anti-counteractive actions"]
["Different targets of the same pathway","17-AAG (heat-shock protein antagonist, induced cell cycle inhibition and apoptosis by inhibiting NF-kappaB, AP-1 and PI3K/Akt pathways (1), Hsp90/FLT3 inhibitor (2))","Arsenic trioxide (degraded aberrant PML-retinoic acid receptor alpha fusion protein, generated reactive oxygen species, and activated Akt survival pathway (3))","Synergistic anticancer effect (3)","Median dose effect analysis (Calcusym)","Arsenic trioxide’s anticancer generation of reactive oxygen species is partially off-set by its own counteractive activation of Akt survival pathway (1). 17-AAG abrogated arsenic trioxide’s activation of Akt survival pathway (1) to reduce the counteractive effect."]
[null,"Oxaliplatin (DNA adduct, preferably bind to major groove of GG, AG and TACT sites, complex conformation different from that of cisplatin (4), caused DNA strand break and non-DNA initiated apoptosis (5))","Irinotecan (DNA topoisomerase I inhibitor, increased EGFR phosphorylation in Lovo & WiDR cells (6))","Synergistic anticancer effect in AZ-521 and NUGC-4 cells, additive effect in MKN-45 cells (7)","Median drug effect analysis","Effect of oxaliplatin’s DNA adduct formation (4) may be partially reduced by certain mutant DNA topoisomerase I acting on DNA adduct to generate different topoisomers (8). Irinotecan inhibition of DNA topoisomerase I (6) partially off-sets this counteractive activity."]
["Different targets of the same pathway that regulated the same target","Cisplatin (DNA inter- and intra- strand adduct, preferably bind to the major groove of GG, AG and TACT sites(9) thereby inhibited DNA polymerization and induced DNA damage to trigger apoptosis (10))","Trabectedin (bind covalently to central G in the minor groove of selected DNA pyrimidine-G-G and purine-G-C triplets (11), formed unusual DNA replication intermediates thereby inhibited DNA replication (12), interacted with DNA and DNA repair systems in a way different from cisplatin (13))","Synergistic antitumor activity (13)","Interaction index method of Berebbaum","Trabectedin inhibition of DNA replication (12) reduced the counteractive activity of DNA polymerase mediated mutagenic translesional bypass replication across cisplatin-DNA adducts (14)."]
[null,"Cisplatin (DNA inter- and intra- strand adduct, preferably bind to the major groove of GG, AG and TACT sites (9) thereby inhibited DNA polymerization and induced DNA damage to trigger apoptosis (10))","Topotecan (topoisomerase I inhibitor, interacted with DNA, stabilized a covalent topoisomerase-DNA complex, thereby blocked DNA replication forks (15))","Synergistic cytotoxic activity (16-18)","Multi-drug effect equation, combination index, median- drug effect method","Topotecan blocking of DNA replication (15) reduced the counteractive activity of mutagenic translesional bypass replication across cisplatin-DNA adducts (14)."]
[null,"Cisplatin (DNA inter- and intra- strand adduct, preferably bind to the major groove of GG, AG and TACT sites (9) thereby inhibited DNA polymerization and induced DNA damage to trigger apoptosis (10))","Sabarubicin (topoisomerase II inhibitor (19))","Synergistic cytotoxic effect in tumour cell lines NSCLC H460 and SCLC GLC4 (20)","Combination index","Sabarubicin blocking of DNA replication (19) reduced the counteractive activity of mutagenic translesional bypass replication across cisplatin-DNA adducts (14)."]
[null,"DL-cycloserine (bacterial cell wall synthesis inhibitor (21))","Epigallocatechin gallate (disrupted integrity of bacterial cell wall via direct binding to peptidoglycan (21))","Synergistic effect on bacterial cell wall (21)","Fractional inhibitory concentration index","Cell wall alteration may induce counteractive cell wall synthesis to restore cell wall integrity (22), DL-cycloserine inhibition of cell wall synthesis hindered the restoration thereby enhanced Epigallocatechin gallate’s cell wall disruption activity."]
[null,"Gefitinib (EGFR tyrosine kinase inhibitor, induced cyclin-dependent kinase inhibitors, inhibited p27 and p21, decreased MMP-2 and MMP-9 enzyme activity (23))","Irinotecan (DNA topoisomerase I inhibitor, increased EGFR phosphorylation in Lovo & WiDR cells (6))","Synergistic inhibitory effect on colorectal cancer Lovo & WiDR cells (6)","Combination index","Irinotecan produced anticancer effect via DNA topoisomerase inhibition, but promoted proliferation by increased phosphorylation of EGFR in certain cell types (6). Gefitinib produced anticancer effect via EFFR tyrosine kinase inhibition and others (23), which offsets the counteractive effect of increased EGFR phosphorylation."]
[null,"Amoxicillin (inhibited bacterial cell wall synthesis (24), destructed by beta-lactamase (25))","Clavulanate (beta-lactamase inhibitor (26))","Antibacterial synergy (27)","Comparison of inhibitory activity","Clavulanate maintained level of amoxicillin at bacterial cell wall by inhibiting its degradation enzyme beta-lactamase inhibitor (26), thereby potentiatived the antibacterial activity of amoxicillin."]
["Different targets of related pathways","17-AAG (heat-shock protein antagonist, induced cell cycle inhibition and apoptosis by inhibiting NF-kappaB, AP-1 and PI3K/Akt pathways (1))","Etoposide (topoisomerase II inhibitor, induced DNA double-strand breaks during DNA replication(28), increased expression of DNA repair-related protein Rad51 (29))","Synergism between etoposide and 17-AAG in leukemia cells (2)","Combination index method (CalcuSyn by BioSoft)","The effect of etoposide’s DNA strand break is partially offset by its own counteractive increase of expression of DNA repair-related protein Rad51 (29). Higher levels of Rad51 and its interacting partner Chk1 are associated with presence of FLT3 (2). Inhibition of Hsp90/FLT3 by 17-AAG may reduce Rad51 and Chk1 to reduce the counteractive effect."]
[null,"Artemisinin (interacted with heme to mediate its decomposition into free radicals that alkylate essential malarial proteins (30))","Methylene blue (inhibited heme polymerization (31-34); glutathione reductase inhibitor, soluble guanylate cyclase inhibitor (35)","Synergistic antimalarial effects in both chloroquine -sensitive and -resistant P. falciparum strains (36)","Isobologram method","Artemisinin's antimalarial activity possibly arise from its interaction with heme that facilitates heme conversion into free radical (31-34), which can be off-set by parasite's counteractive actions of heme polymerization into insoluble hemozoin and heme degradation by glutathione (37). These counteractive actions are partially reduced by methylene blue's inhibition of heme polymerization (31-34) and glutathione reductase, resulting in synergistic antimalarial effect."]
[null,"Erlotinib (EGFR tyrosine kinase inhibitor (38, 39))","Pemetrexed (dihydrofolate reductase, thymidylate synthase and glycinamide ribonucleotide formyl transferase inhibitor (40-42); increased EGFR phosphorylation and reduced Akt phosphorylation (43))","Synergistic cytotoxicity in all cells (43)","Combination-index method","Erlotinib's inhibition of EGFR may trigger activation of Akt-mediated negative-feedback signaling, leading to increased membrane HER3 expression and reduced HER3 phosphatase activity, thereby evading EGFR inhibition (cancer target paper R51). This counteractive action can be partially reduced by pemetrexed's reduction of Akt phosphorylation (43), leading to synergistic effect."]
[null,"Bortezomib (proteasome inhibitor, protected pro-apoptotic pathways by inhibiting proteasome degradation of P53 (44), inhibited NF-kappaB and induced endoplasmic reticulum stress (45))","Sodium butyrate or suberoylanilide hydroxamic acid (Histone deacetylase inhibitor, promoted histone acetylation and chromatin structure relaxation (46), down-regulated expression levels of Bcr-abl, c-Myc and HDAC3 (47); mediated RelA acetylation and NF-kappaB activation (48))","Synergistic apoptosis induction in human multiple myeloma cells (49)","Combination index","HDAC inhibitor's pro-apoptotic down-regulation of Bcr-abl is partially offset by its mediation of NF-kappaB activation (45). This counteractive action can be partially reduced by bortezomib's pro-apoptotic inhibition of NF-kappaB (50)."]
[null,"Lonafarnib (farnesyl transferase inhibitor, inhibited Ras farnesylation (51))","Bortezomib (proteasome inhibitor, protected pro-apoptotic pathways by inhibiting proteasome degradation of P53 (44), inhibited NF-kappaB and induced endoplasmic reticulum stress (45))","Synergistic myeloma- cell death activity (52)","Isobolographic analysis","Bortezomib produced anticancer effect by inhibiting proteasome degradation of P53 (44). But protesome inhibition reduced ubiquitin-dependent cyclin D1 degradation, which hindered Ras-mediated cell growth arrest and apoptosis (53) thereby reduced bortezomib’s anticancer effect. This counteractive activity can be partially offset by lonafamib inhibition of Ras farnesylation (51) that subsequently induced apoptosis by activating the pro-apoptotic protein BAD in BCL2 family (54)."]
[null,"Tamoxifen (estrogen receptor antagonist (55))","Trastuzumab or herceptin (anti-HER-2/neu antibody (56))","Synergistic growth inhibition in ER- positive, HER-2/neu -overexpressing BT-474 breast tumor cells (57, 58)","Combination index","ER crosstalks with EGFR and HER-2/neu (59), signaling via EGFR and HER-2/neu can activate ER and its coactivator AIB1, ER of cell membrane can activate EGFR/HER-2 (58). Anti-HER-2/neu antibody trastuzumab (56) stopped HER-2/neu induced activation of ER and AIB1. ER antagonist tamoxifen (55) stopped ER induced activation of EGFR/HER-2. Use of both drugs reduced the counteractive crosstalks."]
[null,"Rapamycin or deforolimus (mTOR inhibitor (60-62))","CI-1040 or PD0325901 (MEK inhibitor (63))","Synergistic antitumor efficacy in animal models of human lung cancer and in K-RAS mutant, non-V600EB-RAF, B-RAFV600E mutant cell lines (64)","Cell proliferation assay and combination index method of Chou and Talalay","Effects of the inhibition of mTOR by rapamycin or its analogue deforolimus may be partially offset by NPM/ALK-induced mTOR activation that is transduced through the MEK-ERK signaling pathway (65). This countractive action may be reduced by CI-1040 or PD0325901's inhibition of MEK (63)."]
[null,"Paclitaxel (stabilized microtubules via alpha-tubulin acetylation (66) distorted mitosis to trigger apoptosis (67), induced p53 and CDK inhibitors (68), activated caspase-10, caspases-8, -6, and -3, leading to apoptosis (69), activated ERK (70) and CDK2 (71), activated p38 MAP kinase and p53 (72))","NU6140 (CDK inhibitor, down-regulated antiapoptotic protein surviving (73))","Synergistic apoptotic response (73)","Median drug effect analysis","Use of both drugs promoted complementary apoptosis activities via triple actions of surviving down-regulation by NU6140 (73), microtubule stabilization(66) and caspase activation (69) by paclitaxel. Paclitaxel’s promotion of apoptosis may be partially offset by its counteractive pro-growth activation of ERK (70) and CDK2 (71), which may be partially reduced by NU6140’s inhibition of CDK (73)."]
["Different targets of cross-talking pathways","Gefitinib (EGFR tyrosine kinase inhibitor, induced cyclin-dependent kinase inhibitors p27 and p21, decreased MMP-2 and MMP-9 enzyme activity (23))","Taxane (disrupted microtubule by binding to beta-tubulin (74), induced tumor suppressor gene p53 and cyclin-dependent kinase inhibitors P21, down regulated Bcl-2, leading to apoptosis (68))","Strong synergistic effect in breast cancer MCF7/ADR cells (75)","Combination index","Taxane produced anticancer effect by inducing apoptosis (68) and microtubule disruption (74). Crosstalk between EGFR and hypoxia-inducible factor-1alpha pathways increased resistance to apoptosis by up-regulating surviving (76). Gefitinib produced anticancer effect via EFFR tyrosine kinase inhibition, which offsets the counteractive EGFR-hypoxia crosstalk in resisting taxane’s pro-apoptosis activity."]
[null,"Gleevec (inhibitor of c-Abl, p210bcr-abl, c-Kit (77, 78))","L744,832 or LB42918 (farnesyltransferase inhibitor, inhibited Ras farnesylation (79))","Synergistically promoted apoptosis in different imatinib-sensitive and -resistant BCR-ABL-positive CML cells (80))","Median dose effect analysis method of Chou and Talalay","Gleevec inhibition of Abl may leed to selection of resistant mutatons in Bcr-Abl (81), some of the Bcr-Abl mutants bind to Ras associated proteins to activate an alternative Ras mediated tansformation (82) and survival (83) signal. The survival signal involves activation of survival cascades via Ras/Raf/MEK/ERK signaling (83). This counteractive alternative signal may be partially blocked by using farnesyltransferase inhibitor to inhibit Ras farnesylation."]
[null,"Cisplatin (DNA inter- and intra- strand adduct, preferably bind to the major groove of GG, AG and TACT sites (9) thereby inhibited DNA polymerization and induced DNA damage to trigger apoptosis (10))","Trastuzumab or herceptin (anti-HER-2/neu antibody (56))","Synergistic growth inhibition in SNU-216 as an HER2-amplified cell line among gastric cancer cell lines (84)","Isobologram analysis","Cisplatin formed DNA adduct to induce DNA damage and apoptosis, which may be attenuated by DNA repair systems in certain cell types (10). This counteractive DNA repair action may be partially reduced by herceptin's anti-HER2 activitity that suppressed DNA repair pathway known to crosstalk to HER2 (85) and inhibited PI3K-AKT pathway (86) to enhance apoptosis (87)."]
[null,"Dasatinib(inhibitor of c-abl,src, fyn, lck and kit (88, 89))","PKC412 (inhibitor of Flt (90), PKC, VEGFR2, PDGFR, c-kit (91))","Synergistic apoptotic effects in HMC-1.2 cells (92)","Combination index","Inhibition of c-abl and src enhances catalytic activity of some PKC subtypes and their binding to Bcr/Abl in specific cell types (93). Complex of abl with certain PKC subtypes enable communication of ER stress to mitochondria, which is an essential step in subsequent apoptosis (94). This possible counteractive action against dasatinib's inhibition of c-abl and src (88, 89) may be partially alleviated by PKC412's inhibition of PKC (91)."]
["Different targets in the same pathway that crosstalks via other pathway","Gefitinib (EGFR tyrosine kinase inhibitor, induced cyclin-dependent kinase inhibitors p27 and p21, decreased MMP-2 and MMP-9 enzyme activity (23))","PD98059 (MEK inhibiton (95))","Synergistic antitumor effect in breast cancer MDA-MB-361 cells186","Combination index, isobolographic analysis","An autocrine growth loop critical for tumor growth is formed in EGFR-Ras-Raf-MEK-ERK network such that activated MEK activates ERK which upregulates EGFR ligands which promotes the autocrine growth loop (96). This loop produced counteractive activity against gefitinib or PD98059 by reducing the effect of MEK or EGFR tyrosine kinase inhibition. Simultaneous use of both drugs helps disrupting this autocrine growth loop, thereby enhancing each other’s effect."]
["Same target (different sites)","AZT (HIV-1 reverse transcriptase inhibitor (97))","Non-nucleoside HIV-1 reverse transcriptase inhibitor (98)","Antiviral synergism (99)","Isobolographic analysis, Yonetani & Theorell plot","AZT resistance is partly due to phosphorolytical removal of the AZT-terminated primer (100), NNRTI inhibited RT catalyzed phosphorolysis, thereby reduced AZT resistance (99)."]
[]
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