Koteswara Rao Yerra
@engineering.tamu.edu
Biomedical engineering at Texas A&M University
Texas A & M University
RESEARCH, TEACHING, or OTHER INTERESTS
Chemistry, Biotechnology, Biomedical Engineering, Pharmacology, Toxicology and Pharmaceutics
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Tzu‐Ho Chen, Chien‐Ting Chen, Chi‐Fang Lee, Rou‐Jie Huang, Kuan‐Lin Chen, Yuan‐Chun Lu, Suh‐Yuen Liang, Mai‐Truc Pham, Yerra Koteswara Rao, Shih‐Hsiung Wu,et al.
Wiley
Abstract(−)‐Antrocin (1), produced by the medicinal mushroom Antrodia cinnamomea, is a potent antiproliferative compound. The biosynthetic gene cluster of 1 was identified, and the pathway was characterized by heterologous expression. We characterized a haloacid dehalogenase‐like terpene cyclase AncC that biosynthesizes the drimane‐type sesquiterpene (+)‐albicanol (2) from farnesyl pyrophosphate (FPP). Biochemical characterization of AncC, including kinetic studies and mutagenesis, demonstrated the functions of two domains: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to albicanyl pyrophosphate, and the PPase domain then removes the pyrophosphate to form 2. Intriguingly, AncA (94 % sequence identity to AncC), in the same gene cluster, converts FPP into (R)‐trans‐γ‐monocyclofarnesol instead of 2. Notably, Y283/F375 in the TC domain of AncA serve as a gatekeeper in controlling the formation of a cyclofarnesoid rather than a drimane‐type scaffold.
B Sridharan, Y X Zhong, Y K Rao, Y M Tzeng, and M J Lee
IOP Publishing
Abstract Diabetes has been a long-standing disorder and its management has been challenging various medical and research experts for several decades because of its complex causative factors and pathophysiological processes leading to complications. Medicinal plants have been explored in several countries and traditional Chinese medicine is one of the well-recognized alternative treatment methods. In this study, we have chosen some of the underexplored plant parts of Chinese medicinal herbs and analyzed their antioxidant activity and ability to modulate the expression of fibronectin during high glucose conditions. Extraction of the plant materials with different solvent led to 17 extracts and among which, 3 extracts (2, 12 & 17) were observed to render more than 50 μg/ml vitamin C equivalents of DPPH free radical scavenging ability and 2 of them (2 & 17) showed more than 25 μg/ml of vitamin C equivalents of ferric ion reducing power. Based on the antioxidant activity and comparison of their total phenolic content, we used extracts 2 & 17 to check their effect on fibronectin expression in MES-13 cells under high sugar conditions. We observed that both extracts showed a significant reduction of fibronectin expression compared to untreated cells with high glucose levels. The expression was much lesser than the normal untreated, normal sugar supplemented cells and this was not observed in vitamin C supplemented cells. In conclusion, crude extracts containing a group of phenolic compounds have shown significant effects against fibronectin expression leading to reduced ECM deposition and tissue fibrosis. Further exploration might provide insights into the exact mechanism and checkpoints of the extract that can successfully reduce diabetes-induced renal complications.
Chih-Yu Hsieh, Lan-Hui Li, Yulin Lam, Zhanxiong Fang, Chin Heng Gan, Yerra Koteswara Rao, Hsiao-Wen Chiu, Wei-Ting Wong, Tz-Chuen Ju, Fang-Hsin Chen,et al.
MDPI AG
Gouty arthritis results from the generation of uric acid crystals within the joints. These uric acid crystals activate the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, which is involved in chronic inflammatory diseases, including gouty arthritis. This study identified the polyenylpyrrole derivative 4-hydroxy auxarconjugatin B (4-HAB), a novel autophagy inducer, which attenuated uric acid crystals-mediated activation of the NLRP3 inflammasome in vitro and in vivo. 4-HAB dose-dependently reduced the release of interleukin (IL)-1β, IL-18, active caspase-1 and apoptosis-associated speck-like protein (ASC) in uric acid crystals-activated macrophages. In a mechanistic study, 4-HAB was shown to inhibit uric acid crystals-induced mitochondrial damage, lysosomal rupture and ASC oligomerization. Additionally, 4-HAB inhibited the NLRP3 inflammasome through Sirt1-dependent autophagy induction. Furthermore, the anti-inflammatory properties of 4-HAB were confirmed in a mouse model of uric acid crystals-mediated peritonitis by the reduced levels of neutrophil influx, IL-1β, active caspase-1, IL-6 and MCP-1 in lavage fluids. In conclusion, 4-HAB attenuates gouty inflammation, in part by attenuating activation of the NLRP3 inflammasome through the Sirt1/autophagy induction pathway.
Hsiao-Wen Chiu, Lan-Hui Li, Chih-Yu Hsieh, Yerra Koteswara Rao, Fang-Hsin Chen, Ann Chen, Shuk-Man Ka, and Kuo-Feng Hua
Springer Science and Business Media LLC
AbstractThe NLRP3 inflammasome promotes the pathogenesis of metabolic, neurodegenerative and infectious diseases. Increasing evidences show that the NLRP3 inflammasome is a promising therapeutic target in inflammatory diseases. Glucosamine is widely used as a dietary supplement to promote the health of cartilage tissue and is expected to exert anti-inflammatory activity in joint inflammation, which is a nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome-associated complication. Here, we investigated whether GlcN inhibits the NLRP3 inflammasome and dissected the underlying molecular mechanisms. We found that GlcN suppressed the NLRP3 inflammasome in mouse and human macrophages. A mechanistic study revealed that GlcN inhibited the expression of NLRP3 and IL-1β precursor by reducing reactive oxygen species generation and NF-κB activation in lipopolysaccharide-activated macrophages. GlcN also suppressed mitochondrial reactive oxygen species generation and mitochondrial integrity loss in NLRP3-activated macrophages. Additionally, GlcN disrupted NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC. Furthermore, oral administration of GlcN reduced peritoneal neutrophils influx and lavage fluids concentrations of IL-1β, IL-6 MCP-1 and TNF-α in uric acid crystal-injected mice. These results indicated that GlcN might be a novel dietary supplement for the amelioration of NLRP3 inflammasome-associated complications.
Chih‐Yu Hsieh, Lan‐Hui Li, Yerra Koteswara Rao, Tz‐Chuen Ju, Yu‐Shin Nai, Yue‐Wen Chen, and Kuo‐Feng Hua
Wiley
AbstractDysregulation of NACHT, LRR, and PYD domains‐containing protein 3 (NLRP3) inflammasome is involved in many chronic inflammatory diseases, including gouty arthritis. Activation of the NLRP3 inflammasome requires priming and activation signals: the priming signal controls the expression of NLRP3 and interleukin (IL)‐1β precursor (proIL‐1β), while the activation signal leads to the assembly of the NLRP3 inflammasome and to caspase‐1 activation. Here, we reported the effects of the alcoholic extract of Taiwanese green propolis (TGP) on the NLRP3 inflammasome in vitro and in vivo. TGP inhibited proIL‐1β expression by reducing nuclear factor kappa B activation and reactive oxygen species (ROS) production in lipopolysaccharide‐activated macrophages. Additionally, TGP also suppressed the activation signal by reducing mitochondrial damage, ROS production, lysosomal rupture, c‐Jun N‐terminal kinases 1/2 phosphorylation and apoptosis‐associated speck‐like protein oligomerization. Furthermore, we found that TGP inhibited the NLRP3 inflammasome partially via autophagy induction. In the in vivo mouse model of uric acid crystal‐induced peritonitis, TGP attenuated the peritoneal recruitment of neutrophils, and the levels of IL‐1β, active caspase‐1, IL‐6 and monocyte chemoattractant protein‐1 in lavage fluids. As a proof of principle, in this study, we purified a known compound, propolin G, from TGP and identified this compound as a potential inhibitor of the NLRP3 inflammasome. Our results indicated that TGP might be useful for ameliorating gouty inflammation via inhibition of the NLRP3 inflammasome.
Han-Ying Wu, Feng-Ling Yang, Lan-Hui Li, Yerra Koteswara Rao, Tz-Chuen Ju, Wei-Ting Wong, Chih-Yu Hsieh, Michael V. Pivkin, Kuo-Feng Hua, and Shih-Hsiung Wu
Springer Science and Business Media LLC
AbstractAs part of our ongoing search for novel therapeutic structures from microorganism, the chemical examination of marine fungus Phoma sp. resulted in the isolation of ergosterol, ergosterol peroxide (EP), and 9,11-dehydroergosterol peroxide (DEP). The bioassay results demonstrated that the three isolates reduced the viability of various cancer cells, with EP being highest in human lung cancer cell line A549 cells. EP induced caspase-dependent apoptosis through mitochondrial damage in A549 cells. Additionally, EP-induced ROS generation and apoptosis were attenuated by ROS-generating enzymes inhibitors and antioxidant N-acetylcysteine, indicated that ROS played an important role in EP-mediated apoptosis in A549 cells. Furthermore, it was observed that EP induced ROS-dependent autophagy, which attenuated apoptosis in A549 cells. On the other hand, EP reduced the LPS/ATP-induced proliferation and migration of A549 cells through attenuated NLRP3 inflammasome activity. Additionally, EP showed synergistic cytotoxic effect with antitumor drug Sorafenib in A549 cell viability inhibition. Furthermore, Micro-Western Array and Western blot analyses demonstrated that the protein levels of EGFR, HSP27, MEK5, AKT1, mTOR, Smad2, Smad3, TAB1, NF-κB, and HIF1-α decreased, while the levels of p-p38α, p-ERK1/2, p-JNK, fibronectin and p27 increased. Collectively, the results of this study demonstrated that EP might be useful to develop a therapeutic candidate for lung cancer complications.
Wei-Ting Wong, Lan-Hui Li, Yerra Koteswara Rao, Shih-Ping Yang, Shu-Meng Cheng, Wen-Yu Lin, Cheng-Chung Cheng, Ann Chen, and Kuo-Feng Hua
Frontiers Media SA
The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the in vivo mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.
Arifullah Mohammed, Kishore K. Chiruvella, Yerra Koteswara Rao, Madamanchi Geethangili, Sathees C. Raghavan, and Rama Gopal Ghanta
Public Library of Science (PLoS)
Andrographis lineata is an herbal medicinal plant used in traditional medicine as a substitute for Andrographis paniculata. Here, using mature leaf explants of A. lineata we demonstrate for the first time the callus induction established on MS medium containing 1.0 mg l–1 IAA. Dried callus was subjected to solvent extraction with acetone. Further the acetone residue was separated by silica gel column chromatography, crystallized and characterized on the basis of nuclear magnetic resonance (proton and c13) and liquid chromatographic mass spectroscopy. This analysis revealed the occurrence of two known flavones namely, 7-O-methylwogonin (MW) and Echioidinin (ED). Furthermore, these compounds were tested for their cytotoxicity against leukemic cell line, CEM. We identify that ED and MW induced cytotoxicity in a time- and concentration-dependent manner. Further increase in the LDH release upon treatment with ED and MW further confirmed our cytotoxicity results against leukemic cell line. Strikingly, MW was more potent than ED when compared by trypan blue and MTT assays. Our results recapitulate the utility of callus cultures for the production of plant specific bioactive secondary metabolites instead of using wild plants. Together, our in vitro studies provide new insights of A. lineata callus cultures serving as a source for cancer chemotherapeutic agents.
Tung-Cheng Chang, Chi-Tai Yeh, Bamodu Oluwaseun Adebayo, Ying-Chin Lin, Li Deng, Yerra Koteswara Rao, Chun-Chih Huang, Wei-Hwa Lee, Alexander T.H. Wu, Michael Hsiao,et al.
Elsevier BV
Min-Chuan Kao, Yerra Koteswara Rao, Yu-Wen Hsieh, Shih-Hsien Weng, Tzu-Li Lu, David T.W. Tzeng, Jau-Jin Liu, Chun-Jung Lin, Chih-Ho Lai, and Yew-Min Tzeng
Elsevier BV
Yerra Koteswara Rao, Hui-Nung Shih, Yi-Ching Lee, Wen-Tai Cheng, Hui-Chin Hung, Huang-Chi Wang, Ching Jung Chen, Yew-Min Tzeng, and Meng-Jen Lee
Elsevier BV
Thanh-Tuan Huynh, Yerra Koteswara Rao, Wei-Hwa Lee, Hsin-An Chen, T. Do-Quyen Le, David T.W. Tzeng, Liang-Shun Wang, Alexander T.H. Wu, Yuh-Feng Lin, Yew-Min Tzeng,et al.
Elsevier BV
Chi-Tai Yeh, Wen-Chien Huang, Yerra Koteswara Rao, Min Ye, Wei-Hwa Lee, Liang-Shun Wang, David T.W. Tzeng, Chih-Hsiung Wu, Yi-Shing Shieh, Chi-Ying F. Huang,et al.
Oxford University Press (OUP)
Lung cancer is the leading cause of cancer deaths worldwide and current therapies fail to treat this disease in majority of cases. Antrodia camphorata is a medicinal mushroom being widely used as food dietary supplement for cancer prevention. The sesquiterpene lactone antrocin is the most potent among >100 secondary metabolites isolated from A. camphorata. However, the molecular mechanisms of antrocin-mediated anticancer effects remain unclear. In this study, we found that antrocin inhibited cell proliferation in two non-small-cell lung cancer cells, namely H441 (wild-type epidermal growth factor receptor, IC50 = 0.75 μM) and H1975 (gefitnib-resistant mutant T790M, IC50 = 0.83 μM). Antrocin dose dependently suppressed colony formation and induced apoptosis as evidenced by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies indicated that antrocin downregulated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. We further demonstrated that antrocin suppressed both constitutively activated and interleukin 6-induced STAT3 phosphorylation and its subsequent nuclear translocation. Such inhibition is found to be achieved through the suppression of JAK2 and interaction between STAT3 and extracellular signal-regulated kinase. Additionally, antrocin increased microRNA let-7c expression and suppressed STAT signaling. The combination of antrocin and JAK2/STAT3 gene silencing significantly increased apoptosis in H441 cells. Such dual interruption of JAK2 and STAT3 pathways also induced downregulation of antiapoptotic protein mcl-1 and increased caspase-3 expression. In vivo intraperitoneal administration of antrocin significantly suppressed the growth of lung cancer tumor xenografts. Our results indicate that antrocin may be a potential therapeutic agent for human lung cancer cells through constitutive inhibition of JAK2/STAT3 pathway.
Yerra Koteswara Rao, Madamanchi Geethangili, and Yew-Min Tzeng
Royal Society of Chemistry (RSC)
A simple gradient high-performance liquid chromatography with diode array detection (HPLC-DAD) method was developed for the simultaneous determination of total ten triterpenoids in Antrodia camphorata (AC). Optimum separation was obtained with a J'sphere C18 column using gradient elution with 0.2% aqueous acetic acid and acetonitrile as the mobile phase, a flow rate of 0.8 mL min−1, detection wavelength at 248 nm and sample volume at 5 μL. This method produced linear responses for ten triterpenoids in the concentration range of 50–800 μg mL−1. This new method was validated for acceptable precision (intra- and inter-day precision was less than 2.47% and 3.94%, respectively), accuracy (recovery ranged from 96.46% to 102.37%) and sensitivity (LODs and LOQs were in the range of 15.7–50.5 μg mL−1, and 47.8–194.0 μg mL−1, respectively). This method has been successfully applied to the analysis of real AC samples. Quantitation was achieved by direct comparison of the peaks of AC extract of the sample to reference standards of known concentrations. The present results may be useful for evaluating the quality of the AC and its products.
Yerra Koteswara Rao, Yu-Ching Chen, Shih-Hua Fang, Chih-Ho Lai, Madamanchi Geethangili, Chen-Chen Lee, and Yew-Min Tzeng
Elsevier BV
Chun-Jung Lin, Yerra Koteswara Rao, Chiu-Lien Hung, Chun-Lung Feng, Hsien-Yuan Lane, David T. W. Tzeng, Ping-Ning Hsu, Chih-Ho Lai, and Yew-Min Tzeng
Hindawi Limited
The bacterial pathogenHelicobacter pylori(Hp) is the leading risk factor for the development of gastric cancer. Hp virulence factor, cytotoxin-associated gene A (CagA) interacted with cholesterol-enriched microdomains and leads to induction of inflammation in gastric epithelial cells (AGS). In this study, we identified a triterpenoid methylantcinate B (MAB) from the medicinal mushroomAntrodia camphoratawhich inhibited the translocation and phosphorylation of CagA and caused a reduction in hummingbird phenotype in HP-infected AGS cells. Additionally, MAB suppressed the Hp-induced inflammatory response by attenuation of NF-κB activation, translocation of p65 NF-κB, and phosphorylation of IκB-α, indicating that MAB modulates CagA-mediated signaling pathway. Additionally, MAB also suppressed the IL-8 luciferase activity and its secretion in HP-infected AGS cells. On the other hand, molecular structure simulations revealed that MAB interacts with CagA similarly to that of cholesterol. Moreover, binding of cholesterol to the immobilized CagA was inhibited by increased levels of MAB. Our results demonstrate that MAB is the first natural triterpenoid which competes with cholesterol bound to CagA leading to attenuation of Hp-induced pathogenesis of epithelial cells. Thus, this study indicates that MAB may have a scope to develop as a therapeutic candidate against Hp CagA-induced inflammation.
Ya-Fan Liao, Yerra Koteswara Rao, and Yew-Min Tzeng
Elsevier BV
Chi-Tai Yeh, Yerra Koteswara Rao, Min Ye, Wen-Shi Wu, Tung-Chen Chang, Liang-Shun Wang, Chih-Hsiung Wu, Alexander T.H. Wu, and Yew-Min Tzeng
Elsevier BV
Yerra Koteswara Rao, Hsiu-Man Lien, Yu-Hsin Lin, Yuan-Man Hsu, Chi-Tai Yeh, Chia-Chang Chen, Chih-Ho Lai, and Yew-Min Tzeng
Elsevier BV
Yew-Min Tzeng, Yi-Ching Lee, Wen-Tai Cheng, Hui-Nung Shih, Huang-chi Wang, Yerra Koteswara Rao, and Meng-Jen Lee
Elsevier BV
Yun-Chih Hsieh, Yerra Koteswara Rao, Jacqueline Whang-Peng, Chi-Ying F. Huang, Song-Kun Shyue, Shih-Lan Hsu, and Yew-Min Tzeng
American Chemical Society (ACS)
The triterpenoids methylantcinate B (MAB) and antcin B (AB), isolated from the medicinal mushroom Antrodia camphorata , have been identified as strong cytotoxic agents against various type of cancer cells; however, the mechanisms of MAB- and AB-induced cytotoxicity have not been adequately explored. This study investigated the roles of caspase cascades, reactive oxygen species (ROS), DNA damage, mitochondrial disruption, and Bax and Bcl-2 proteins in MAB- and AB-induced apoptosis of hepatocellular carcinoma (HCC) HepG2 cells. Here, we showed that MAB and AB induced apoptosis in HepG2 cells, as characterized by increased DNA fragmentation, cleavage of PARP, sub-G1 population, chromatin condensation, loss of mitochondrial membrane potential, and release of cytochrome c. Increasing the levels of caspase-2, -3, -8, and -9 activities was involved in MAB- and AB-induced apoptosis, and they could be attenuated by inhibitors of specific caspases, indicating that MAB and AB triggered the caspase-dependent apoptotic pathway. Additionally, the enhanced apoptotic effect correlates with high expression of Fas, Fas ligand, as well as Bax and decreased protein levels of Bcl-(XL) and Bcl-2, suggesting that both the extrinsic and intrinsic apoptosis pathways were involved in the apoptotic processes. Incubation of HepG2 cells with antioxidant enzymes superoxide dismutase and catalase and antioxidants N-acetylcysteine and ascorbic acid attenuated the ROS generation and apoptosis induced by MAB and AB, which indicate that ROS plays a pivotal role in cell death. NADPH oxidase activation was observed in MAB- and AB-stimulated HepG2 cells; however, inhibition of such activation by diphenylamine significantly blocked MAB- and AB-induced ROS production and increased cell viability. Taken together, our results provide the first evidence that triterpenoids MAB and AB induced a NADPH oxidase-provoked oxidative stress and extrinsic and intrinsic apoptosis as a critical mechanism of cause cell death in HCC cells.
Yerra Koteswara Rao, Meng-Jen Lee, Keru Chen, Yi-Ching Lee, Wen-Shi Wu, and Yew-Min Tzeng
Wiley
Citrus grandis (L.) Osbeck (red wendun) leaves have been used in traditional Chinese medicine to treat several illnesses including diabetes. However, there is no scientific evidence supporting these actions and its active compounds. Two flavone glycosides, rhoifolin and cosmosiin were isolated for the first time from red wendun leaves and, identified these leaves are rich source for rhoifolin (1.1%, w/w). In differentiated 3T3‐L1 adipocytes, rhoifolin and cosmosiin showed dose‐dependent response in concentration range of 0.001–5 μM and 1–20 μM, respectively, in biological studies beneficial to diabetes. Particularly, rhoifolin and cosmosiin at 0.5 and 20 μM, respectively showed nearly similar response to that 10 nM of insulin, on adiponectin secretion level. Furthermore, 5 μM of rhoifolin and 20 μM of cosmosiin showed equal potential with 10 nM of insulin to increase the phosphorylation of insulin receptor‐β, in addition to their positive effect on GLUT4 translocation. These findings indicate that rhoifolin and cosmosiin from red wendun leaves may be beneficial for diabetic complications through their enhanced adiponectin secretion, tyrosine phosphorylation of insulin receptor‐β and GLUT4 translocation.
Yerra Koteswara Rao, Alexander T. H. Wu, Madamanchi Geethangili, Ming-Te Huang, Wan-Ju Chao, Chih-Hsiung Wu, Win-Ping Deng, Chi-Tai Yeh, and Yew-Min Tzeng
American Chemical Society (ACS)
The PI3K/Akt/mTOR pathway is considered to be an attractive target for the development of novel anticancer molecules. This paper reports for the first time that a small molecule, antrocin (MW = 234), from Antrodia camphorata was a potent antagonist in various cancer types, being highest in metastatic breast cancer MDA-MB-231 cells (MMCs) with an IC(50) value of 0.6 μM. Antrocin was a superior antiproliferator in MMCs as compared with doxorubicin and cisplatin, prevents colony formation, and was nontoxic to nontumorgenic MCF10A and HS-68 cells. Antrocin induced dose-dependent apoptosis in MMCs and caused cleavage of caspase-3 and poly(ADP-ribose) polymerase. Antrocin also caused a time-dependent decrease in protein expression of anti-apoptotic Bcl-2, Bcl-xL, survivin, and their mRNA, with concomitant increase in pro-apoptotic Bax and cytosolic cytochrome c. In a mechanistic study, antrocin suppressed the phosphorylation of Akt and its downstream effectors mTOR, GSK-3β, and NF-κB. Furthermore, down-regulation of Akt by small interfering RNA prior to antrocin treatment resulted in enhanced cell growth inhibition and apoptosis. Thus, antrocin as an Akt/mTOR dual inhibitor has broad applicability in the development of a clinical trial candidate for the treatment of metastatic breast cancer.