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[]
["TTD - Therapeutic Targets Database"]
["Version 4.3.02 (2011.08.25)"]
["File Name: Pharmacodynamically synergistic drug combinations due to complementary actions."]
["Synergy has been determined by well established synergy/additive analysis methods and its molecular mechanism has been revealed."]
[]
["Combination target relation","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 promoting complementary actions"]
["Different targets of the related pathways that regulate the same targets","17-AAG (Inhibited Hsp90/FLT3 (1), which degraded ALK and Akt, dephosphorylated ERK, downregulated cyclin D1, CDK4, and CDK6 in ALCL cells (2), heat-shock protein antagonist, induced cell cycle inhibition and apoptosis by inhibiting NF-kappaB, AP-1 and PI3K/Akt pathways (3))","U0126 (MEK1/2 inhibitor)","17-AAG synergizes with U0126 in ALCL irrespective of ALK expression (2)","Combination index and isobologram from Chou-Talalay method (Calcusyn by Biosoft)","Activated ERK promotes ALCL cell survival. HSP90 is abundantly expressed in ALCL cells. 17-AAG produced its effect on ALCL cells by inhibiting Hsp90/FLT3 which dephosphorylated ERK (2). Such an action is complemented by U0126’s inhibition of MEK1/2 which inhibited ERK (2)."]
[null,"ABT-737(Bcl-2 family proteins Bcl-2, Bcl-xL inhibitor (4))","Dexamethasone (down-regulatied Bcl-2 and Bcl-xL (5))","Synergistic effect in inducing myeloma cell death (4)","Combination Index","ABT-738’s inhibition of Bcl-2 and Bcl-xL (4) is complemented by dexamethasone ‘s down-regulation of Bcl-2 and Bcl-xL (5)."]
[null,"Azithromycin (hindered bacterial protein synthesis by binding to 50S component of 70S ribosomal subunit (6))","Ceftazidime (blocked penicillin-binding proteins and thus bacterial cell wall synthesis (7))","Synergistic antibacterial effect (8)","Checkerboard method, fractional inhibitory concentration","Hindered protein synthesis by azithromycin (6) reduces penicillin-binding proteins to complement ceftazidime’s blocking of penicillin-binding proteins (7)."]
[null,"Bortezomib(inhibited proteasome and NF-kappaB (9))","Trastuzumab (herceptin) (anti-HER-2/neu antibody (10))","Synergistic apoptosis effect in HER-2 positive breast cancer cell lines (11)","Combination Index","Bortezomib's inhibition of NF-kappaB (9) is complemented by herceptin's inhibition of HER-2 receptor (11) that subsequently blocks EGF-induced NF-kappaB activation (12)."]
[null,"Gleevec (selective inhibitor of c-Abl, p210bcr-abl, c-Kit, and PDGF-R tyrosine kinases (13, 14))","Histone deacetylase inhibitor (promoted histone acetylation and chromatin structure relaxation (15); down-regulated Bcr-abl, c-Myc and HDAC3 (16))","Synergistically induced apoptosis in STI571-resistant K562 and LAMA 84 cells (17)","Combination index","Gleevec 's pro-apoptotic inhibition of Abl (13, 14) may be partially complemented by Histone deacetylase inhibitor's down-regulation of Bcr-abl (16)."]
[null,"Rapamycin (mTOR inhibitor (18-20); targeted transcription factor yy1 to down-regulate mitochondrial transcriptional regulators PGC-1","3-BrOP (inhibited glycolysis by inactivating hexokinase, a key enzyme in the glycolytic pathway (22))","Synergistically impacted energy metabolism in cancer cells (22)","Combination Index","mTOR inhibition by rapamycin further compromised the ability of cells to uptake glucose when the glycolytic pathway is inhibited by 3-BrOP (22), which is partly due to the down-regulation of nuclear respiratory factors by 3-BrOP (21) that down-regulated glycolytic and mitochondrial oxidative proteins (23)."]
[null,", oestrogen-related receptor alpha and nuclear respiratory factors (21)"]
[null,"Triclosan (E.coli fabI inhibitor, antimicrobial activity (24))","Antisense drug Ec106fabI targeting mRNA of E.coli fabI (24)","Some combinations of protein inhibitor and antisense drug of shared genetic target satisfy conservative definition of antimicrobial synergy (24)","Checkerboard method, fractional inhibitory concentration indices","Joint inhibition and reduction of bacterial protein."]
[null,"Celecoxib (COX-2 inhibitor, inactivated protein kinase Akt to stop its suppression of apoptosis, it also inhibited ER Ca2+ ATPase (25))","Emodin (tyrosine kinase inhibitor (26), down-regulated protein kinase Akt via inhibition of components of the PI3K pathway to reduce AKT suppression of apoptosis (27))","Synergistically suppressed growth of certain tumor cells (28)","Isobolographic analysis, fractional inhibition method, Zhang method","In addition to its antitumor activity via tyrosine kinase inhibition, emodin down-regulated Akt (27) to complement celecoxib’s inactivation of Akt (25) to reduce Akt’s suppression of apoptosis."]
["Different targets of the related pathways that regulate the same process","17-DMAG (Inhibited Hsp90, which prevented stabilization of \"client\" cancer targets such as mutated p53, Raf-1, ErbB2, and other signaling proteins (29), thereby induced apoptosis and growth arrest in certain carcinoma cells (30). Attenuated STAT3 and phospho-ERK level(31)","Arsenic trioxide (inhibited thioredoxin reductase leading to apoptosis, which is the basis for its anticancer activity (32), down-regulated constitutive STAT3 activity in AML cells (29)","ATO and Hsp90 inhibitor 17-DMAG showed synergistic interactions in inhibiting constitutive STAT3 activity and inducing cell death, in spite of a concurrent synergistic up-regulation of HSP70 (29)","Isobologram","Both drugs complement each other’s activity by inducing apoptosis via Hsp90 (29) and thioredoxin reductase inhibition (32). Moreover, both drugs down-regulated the constitutive STAT3 (29, 31), which are over-expressed in 50% of AML cases."]
[null,"Aplidin (induced apoptosis by activating and clustering death receptors FasL (33), activating JNK, EGFR, Src, and p38MAPK (34), inhibited VEGF release and secretion (35))","Cytarabine (DNA binder (36), inhibited synthesome associated DNA polymerase alpha activity (37), inhibited RNA synthesis and DNA repair that lead to increased cellular stress and reduced survival protein Mcl-l which subsequently activate caspase and apoptosis (38))","Aplidin synergizes with cytarabine in exhibiting anticancer activities in leukemia and lymphoma models in vitro and in vivo (39)","Chou-Talelay combination index (Calcusym Biosoft)","Both drugs complement each other’s activity by inducing apoptosis via each of the two major cascades of apoptosis pathway, aplidin activated and clusterd death receptors of FasL (33) which subsequently activates the receptor-mediated extrinsic cascade (40), cytarabine increased cellular stress and reduced survival protein Mcl-1 (38) which subsequently triggers the mitochondrial intrinsic cascade (40)."]
["Different targets of the same pathway that regulate the same target","Paclitaxel (stabilized microtubules via alpha-tubulin acetylation (41), distorted mitosis to trigger apoptosis (42) and induce p53 and CDK inhibitors (43))","Lonafarnib (farnesyl transferase inhibitor, inhibited Ras farnesylation, microtubule associated alpha-tubulin deacetylase (44), and P-gp (45), metabolized by CYP3A4 and CYP3A5 (46))","Synergistically inhibited deacetylating activity of tubulin decaetylase (47)","Thin plate spline method","Both drugs complement each other’s microtubule stabilization effects through enhanced acetylation activity of alpha-tubulin by paclitaxel (41) and reduced deacetylation activity of alpha-tubulin deacetylase by lonafarnib (44)."]
[null,"Paclitaxel (stabilized microtubules via alpha-tubulin acetylation (41), distorted mitosis to trigger apoptosis (42) and induce p53 and CDK inhibitors (43))","Tubacin (histone deacetylase 6 inhibitor, inhibited microtubule associated alpha-tubulin deacetylase activity (48))","Synergistically enhanced tubulin acetylation (44)","Combination index (Calcusym)","Both drugs complement each other’s microtubule stabilization effects through enhanced acetylation activity of alpha-tubulin by paclitaxel (41) and reduced deacetylation activity of alpha-tubulin deacetylase by tubacin (48)."]
[]
[null,"Paclitaxel (stabilized microtubules via alpha-tubulin acetylation (41), distorted mitosis to trigger apoptosis (42) and induce p53 and CDK inhibitors(43))","Trichostatin (histone deacetylase inhibitor, inhibited microtubule associated alpha-tubulin deacetylase activity (44), acetylated core histones at PTEN promoter thereby induced PTEN transcription leading to enhanced apoptosis (49), induced cyclin-dependent kinase inhibitor p21 (50) thereby induced G1 arrest and blocked entry into S phase (51))","Synergistic effects on apoptosis and microtubule stabilization (52)","Individual/combination response preprocessing and comparative analysis","These drugs complement each other by two actions. One jointly promotes apoptosis by triggering it via aberrant mitosis (paclitaxel) (42) and by enhancing it via upregulating PTEN (trichostatin) (49). The other involves microtubule stabilization by enhanced acetylation activity of alpha-tubulin (paclitaxel) (41) and reduced deacetylation activity of alpha-tubulin deacetylase trichostatin (44)."]
["Different targets of related pathways that regulate the same target","5-AZA-2’-deoxycytidine (DNA methyltransferase -1 and -3B inhibitor, stopped silencing of the pro-apoptotic BI (53))","Fluorouracil (metabolite inhibited thymidylate synthase that stopped DNA synthesis (54), stabilized and activated P53 by blocking MDM2 feedback inhibition through ribosomal proteins (55))","Synergistic effect of 5-Aza-2'-deoxycytidine and 5-fluorouracil on drug-resistant tumors",null,"5-AZA-2’-deoxycytidine inhibition of DNA methyltransferase -1 and -3B stopped silencing of tumor suppressor gene, pro-apoptotic BIK, in cancer cells (53). Fluorouracil stabilized and activated P53 (55), activation of P53 upregulated BIK (56) which complements 5-AZA-2’-deoxycytidine’ un-silencing of BIK."]
[null,"5-AZA-2’-deoxycytidine (DNA methyltransferase -1 and -3B inhibitor, stopped silencing of the pro-apoptotic BIK (53))","Depsipeptide (histone deacetylase inhibitor, induced the pro-apoptotic BIK (53))","Synergistic antineoplastic effect (57)","Valeriote & Lin’s comparative analysis method","5-AZA-2’-deoxycytidine inhibition of DNA methyltransferase -1 and -3B stopped silencing of tumor suppressor gene, pro-apoptotic BIK, in cancer cells to complement depsipeptide’s induction of the same gene (53)."]
[null,"Gefitinib (EGFR tyrosine kinase inhibitor, induced cyclin-dependent kinase inhibitors p27 and p21, decreased MMP-2 and MMP-9 enzyme activity (58))","ST1926 (activated MAP kinases p38 and JNK, released cytochrome c, activated caspase proteolytic cascade (59))","Synergistic modulation of survival signaling pathways (60)","Combination Index","Gefitinib 's inhibition of EGFR is complemented by ST1926's activation of MAP kinases p38 (59) that subsequently mediates internalization of EGFR (61), and by ST1926's activation of caspase proteolytic cascade (59)."]
["Different targets of related pathways","Fluorouracil (metabolite inhibited thymidylate synthase that stopped DNA synthesis (54), stabilized and activated P53 by blocking MDM2 feedback inhibition through ribosomal proteins (55))","RPR-115135 (farnesyl transferase inhibitor, inhibited Ras farnesylation (62))","Synergistic cytotoxic effect (63)","Combination index","Joint tumor suppressive (via fluorouracil stabilization of P53 (55)) and antiproliferative (via RPR-115135 inhibition of Ras farnestlation (62)) actions."]
[null,"CP55940 (cannabinoid agonist, elicited analgesic effects in acute and chronic pain states via spinal and supraspinal pathways (64))","Dexmedetomidine (alpha2 adrenoceptor agonist, activated endogenous nonrapid eye movement sleep-promoting pathways (65))","Significant antinociception synergy in some cases","Isobolographic analysis","Cannabinoid agonist modulated spinal and supraspinal pathways (64) that regulate pain (66) , dexmedetomidine promoted sleepiness (65) that sustains reduction in spike activity of spinoreticular tract neurons (67)."]
[null,"Dipropofol (inhibited bacterial protein synthesis or amino acid incorporation (68))","Vancomycin (blocked transglycosylation and transpeptidation reactions in polymerization of bacterial cell wall peptidoglycan, thereby inhibited cell wall biosynthesis (69))","Synergism against vancomycin resistant bacterial strains (68)","Checkerboard method","Hindered protein synthesis by dipropofol (68) might reduce cell-wall synthesis proteins and thus complement vancomycin’s inhibition of cell wall."]
[null,"Tipifarnib (farnesyl transferase inhibitor, inhibited Ras farnesylation, upregulated death receptor 5, a p53 target gene and receptor of TRAIL (70), inhibited P-gp (71))","Zoledronic acid (activated caspase 3 and fragmented PARP to induce apoptosis, reduced Ras activity and antagonized its stimulation by EGF (72))","Strong synergism in growth inhibition and apoptosis (72)","Combination index (Calcusym)","Joint anti-growth activities via tipifarnib inhibition of Ras farnesylation (70) and zoledronic acid reduction of Ras activity (72), joint apoptosis activities via tipifarnib upregulation of death receptor 5 (70) and zoledronic acid activation of caspase 3 (72), upregulation of death receptor helps to activate capspases (73))."]
[null,"Paclitaxel (stabilized microtubules via alpha-tubulin acetylation (41) distorted mitosis to trigger apoptosis (42) and induce p53 and CDK inhibitors (43), activated caspase-10, caspases-8, -6, and -3, leading to apoptosis (74), activated ERK (75) which in turn activates CDK2 (76), activated p38 MAP kinase and p53 (77))","NU6140 (CDK inhibitor, down-regulated antiapoptotic protein surviving (78))","Synergistic apoptotic response (78)","Median drug effect analysis","Use of both drugs promoted complementary apoptosis activities via triple actions of surviving down-regulation by NU6140 (78), microtubule stabilization (41) and caspase activation (74) by paclitaxel. Paclitaxel’s promotion of apoptosis may be partially offset by its counteractive pro-growth activation of ERK (75) and CDK2 (76), which may be partially reduced by NU6140 via its inhibition of CDK (78)."]
[null,"Sildenafil (phosphodiesterase-5 inhibitor (79))","Iloprost (prostacyclin receptor agonist leading to vascular relaxation (80), activated phospholipase C (81) that promoted VEGF-induced skin vasorelaxation (82), self-regulated endothelial cell adhesion molecules (83))","Synergistic action to cause strong pulmonary vasodilatation (84)","Dose effect curve surpassed that of individual drug alone combined","Sildenafil produced vasodilation activity by inhibiting phosphodiresterase-5 (79), iloprost produced vasodilation activity by agonizing prostacyclin receptor (80) and by activating phospholipase C (81). Targeting of multiple vasodilatation regulation pathways NO/cGMP(85), MaxiK channel -mediated relaxation (86), and phospholipase C (81) contribute to the synergistic actions."]
[null,"Dexmedetomidine (alpha2A receptor agonist, produced antinociceptive effect via an endogenous sleep-promoting pathway (65))","ST-91 (agonist of alpha2 receptor of other subtypes, produced antinociceptive effect via upraspinal receptors and at both spinal and brainstem levels of the acoustic startle response pathway (87))","Synergistic antinociceptive action (88, 89)","Isobolographic analysis","ST-91 modulated spinal and supraspinal pathways (87) that regulate pain (66) , dexmedetomidine promoted sleepiness (65) that sustains reduction in spike activity of spinoreticular tract neurons (67)."]
["Different target subtypes of related pathways","Mycophenolate mofetil (inosine monophosphate dehydrogenase inhibitor, drug metabolite mycophenolic acid binds to the site of nicotinamide adenine dinucleotide cofactor (90))","Mizoribine (inosine monophosphate dehydrogenase inhibitor, drug metabolite mizoribine monophosphate binds to the enzyme in transition state having a new conformation (91))","Mild synergistic suppression of T and B cell proliferation (92)","Median drug effect analysis, Combination index","Simultaneous inhibition of enzyme reactant-state and transition state have the advantage of covering more conformational space for the inhibitors to better compete with natural substrates for the binding sites."]
["Same target (different states)","Paclitaxel (stabilized microtubules via alpha-tubulin acetylation (41), distorted mitosis to trigger apoptosis (42) and induce p53 and CDK inhibitors (43))","Discodermolide (stabilized microtubule dynamics and enhanced microtubule polymer mass (93) resulting in aberrant mitosis that triggers apoptosis (42) and induced p53 and CDK inhibitors (43), retained antiproliferative activity against carcinoma cells resistant to paclitaxel due to beta-tubulin mutations (94))","Antiproliferative synergy (95)","Combination index","Explanation 1: Binding sites of both drugs overlapping, certain mutations resistant to one drug are ineffective against the other, thereby covering more diverse range of mutant types (96-98). Explanation 2: One drug binds and induces conformational change in tubulin that increases the binding affinity of the other (98, 99). Explanation 3: These drugs may differentially bind to or affect different tubulin subtypes, microtubule architectures, or microtubule regulators, thereby covering more diverse range of microtubule dynamics (98-101)."]
["Same target (overlapping binding sites)","Paclitaxel (stabilized microtubules via alpha-tubulin acetylation (41), distorted mitosis to trigger apoptosis (42) and induce p53 and CDK inhibitors (43))","Peloruside A (binds at a different site from that of paclitaxel, stabilized microtubules via binding to a unique site on the tubulin alpha, beta heterodimer (102))","Peloruside A synergizes with paclitaxel to enhance the antimitotic action of the drugs (102)","Berenbaum’s combination index","Explanation 1: Binding sites of both drugs overlapping, certain mutations resistant to one drug are ineffective against the other, thereby covering more diverse range of mutant types (96-98). Explanation 2: One drug binds and induces conformational change in tubulin that increases the binding affinity of the other (98, 99). Explanation 3: These drugs may differentially bind to or affect different tubulin subtypes, microtubule architectures, or microtubule regulators, thereby covering more diverse range of microtubule dynamics (34, 98, 99, 101)."]
["Same target (different binding sites)","Paclitaxel (external DNA binder with partial helix stabilization without altering B-form, binds to A-T, G-C bases and the backbone PO(2) groups (103), interacted with DNA topoisomerase I (104))","Trabectedin (formed DNA adduct at the central G in minor groove of pyrimidine-G-G and purine-G-C triplets that stabilizes duplex DNA to hamper strand separation and stall replication and transcription forks (105), induced topoisomerase I mediated protein-linked DNA breaks (106), traped protein from the nucleotide-excision repair system resulting in DNA damage (107), induced transient p53 elevation (108), and it is a P-gp substrate (109))","Synergistic cytotoxicity (110)","Isobolographic analysis, Chou-Talalay equation","Both drugs enhance each other’s effect by two actions: (1) binding to different sites of DNA at mutually compatible conformation, thereby complement each other on their blocking of DNA polymerase and transcription processes (103, 105)(2) these bindings facilitated interaction with DNA topoisomerase I (104) and its DNA breaking actions (106). "]
[null,"Cisplatin (DNA inter- and intra- strand adduct, preferably bind to the major groove of GG, AG and TACT sites (111) thereby inhibited DNA polymerization and induced DNA damage to trigger apoptosis (112))","Cyclophosphamide (metabolite formed DNA adduct at phosphoester (113) and at G N-7 positions (114), thereby inhibited DNA polymerization and induced DNA damage to trigger apoptosis (115))","Combination produced response rates of 60% to 80% in small cell lung cancer patients (116))","Comparison of activity","Cisplatin and cyclophosphamide formed DNA adduct at different sites (112, 113) possibly at mutually compatable binding conformation because of the small size of the drugs, thereby complementing each other’s actions on DNA."]
[null,"Diclofenac (non-selective COX inihibitor (117), COX1 inhibition increased brain KYNA formation to produce analgesic effect (117))","Paracetamol (major ingredient of Tylenol and Panadol, metabolite agonized cannabinoid receptors to produce analgesic effect(118),(119), reduced active oxidized form of COX to resting form (120), selective COX2 variant inhibitor (121))","Synergy in treatment of acute pain in humans (122)","Isobolographic analysis","Apart from its analgesic action via cannabinoid receptors (118, 119), paracetamol reduced active oxidized form of COX to resting form (120) to complement diclofenac’s analgesic action of COX1 inhibition (117)."]
[]
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