Leptosins isolated from marine fungus Leptoshaeria species inhibit DNA topoisomerases I and/or II and induce apoptosis by inactivation of Akt/protein kinase B

Abstract

(1-4) Class I enzymes (topo I, EC 5.99.1.2) act by making a transient break in one DNA strand, allowing the DNA to swivel and release torsional strain, changing the linking number by steps of one.(2,4) Class II enzymes (topo II, EC 5.99.1.3) make transient breaks in both strands of one DNA molecule, allowing the passage of another DNA duplex through the gap, changing the linking number by steps of two.(1-3) These enzymes are crucial for cellular genetic processes such as DNA replication, transcription, recombination, and chromosome segregation at mitosis.It has long been accepted that topos are valuable targets of cancer chemotherapeutics.(2-5) Several classes of topo inhibitors have been introduced into cancer clinics as potent anticancer drugs, including camptothecin (CPT) derivatives (e.g. irinotecan and topotecan) inhibiting topo I (4) and anthracyclines (e.g. doxorubicin and mitoxantorone), epipodophyllotoxins (e.g. etoposide , aminoacridines (e.g. m-AMSA) and ellipticines targeting topo II.(4,5) These agents are active in both hematological and solid malignancies. The activity of these agents is thought to result from stabilization of the DNA /topo cleavable complex (CC), an intermediate in the catalytic cycle of the enzymes, (2,5,6) resulting ultimately in apoptosis. A number of new topo inhibitors have recently been reported that do not stabilize CC. Thus, two general mechanistic classes of topo inhibitors, especially for topo II, have recently been described: (7) (1) classical topo 'poisons' that stabilize CC and stimulate single-or double-strand cleavage of DNA, such as CPT and its derivatives, indolocarbazoles for topo I, and for topos I and II; and (2) catalytic inhibitors that prevent the catalytic cycle of the enzymes at steps other than cleavage intermediates, such as dioxopiperazines, (7,9,10) aclarubicin, (11) intoplicin, (12) and F11782.(13) Some of these compounds are dual inhibitors of topos I and II. The catalytic inhibitors of topo II, merbarone (14,15) and dioxopiperazines, (9,10) have been extensively studied and have been shown to inhibit the reopening of the closed clamp formed by the enzyme around DNA by inhibiting the ATPase activity of the enzyme, thus sequestering the enzyme within the cell. (7,16,17)

Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride

“…It has been reported that CPT-11 can induce the caspase-3 activity through down-regulation of the phosphatidylinositol 3-kinase [PI(3)K]-Akt signal pathway, which leads induction of apoptotic cell death (15). In wild-type cells, the protein abundance of phosphorylated Akt (p-Akt) was obviously decreased by treatment of the cells with DEX or CPT-11 ( Fig.…”

“…On the other hand, the cytotoxic effect of CPT-11 is also caused by the promotion of apoptotic cell death through down-regulation of the PI(3)K-Akt survival pathway (15). The serine / threonine kinase Akt is a downstream effector of PI(3)K that is recognized as the major mediator of survival signals that protect cells from undergoing apoptosis (18).…”

Dual inhibition: a novel promising pharmacological approach for different disease conditions

“…), tafluposide (F 11782), a novel epipodophylloid, and XR11576, a novel phenazine. [46][47][48][49][50] …”

“…Dual monoamine oxidase B inhibitors and adenosine A2A receptor antagonists Methylxanthines [26] and (E,E)-8-(4-phenylbutadien-1-yl)caffeine [27] Inflammation Dual cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) inhibitors Flavocoxid [28] and ML3000 (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-H-pyrrolizine-5-yl) acetic acid [29] Hypertension Dual inhibitors of neprilysin and angiotensin-converting enzyme BMS-182657, [30] MDL-100173 [31] and S21402 (RB105) {N-[2S,3R-(2-mercaptomethyl-1-oxo-3-phenylbutyl)-l-alanine]} [32] Dual inhibitors of the angiotensin II receptor and neprilysin LCZ696 [33] Dual inhibitors of angiotensin-converting and endothelin-converting enzymes CGS 26303 [34] and SLV 306 (Daglutril) [35] Dual vasopressin receptor (V1/V2) antagonists (RWJ-676070) [36] Thrombosis Dual-acting anticoagulant/antiplatelet inhibitors MC45301, MC45308, MC45350, and MC45403 derived from vitamin B6 (pyridoxine) [37] Microbial infections Dual inhibitors of type I and type II DNA topoisomerases Some novel indolyl quinoline analogs [38] Dual inhibitors of b-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) Platencin [39] Viral infections Dual inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H Madurahydroxylactone derivatives [40] Dual inhibitors of 2A and 3C proteases encoded by human rhinoviruses (HRVs) LY343814 [41] Cancer Dual PI3K and mTOR inhibitors PI-103, [42] NVP-BEZ235, [43] WJD008 [44] and BAG956 [45] Dual topoisomerases I and II inhibitors Benzophenanthridine alkaloids, indolocarbazoles and lipophilic bis(naphthalimides), anthraquinones, pyridoindoles, indenoquinolones, acridines, TAS-103, leptosins (Leps) F and C, tafluposide (F 11782) and XR11576 [46][47][48][49][50] Dual inhibitors of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 NVP-AEE788 [51] Dual inhibitors of IkappaB kinase-2 (IKK2) and Fms-like tyrosine kinase 3 (FLT3) AS602868 [52] The new hybrids retain the potent and selective human AChEinhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in-vitr...…”

Mycochemistry of marine algicolous fungi

“…As a result, leptosins C (258) and F (261) were found to be catalytic inhibitors of topo I and be able to inhibit the Akt pathway. Especially, 258 possesses the in vivo catalytic inhibition of topo I and can induce apoptosis in RPMI8402 cells by accumulation of cells in sub-G1 phase, activation of caspase-3, and degradation of chromosomal DNA (Yanagihara et al 2005). Additionally, leptosin M (271) showed appreciable inhibition of a panel of human cancer cell lines from breast, CNS, colon, lung, melanoma, ovary, kidney, stomach, and prostate with a mean GI 50 value of 5.62 μM (Yamada et al 2002).…”