Abstract
Reported cases of breast cancer have skyrocketed in the last decades with recent advances in examination techniques. Brest cancer has become the second leading cause of mortality among women worldwide, urging the scientific community to develop or find new drugs from natural sources with potent activity and a reasonable safety profile to tackle this ailment. Antrodia cinnamomea (AC) is a treasured medicinal fungus which has attracted attention due to its potent hepatoprotective and cytotoxic activities. We evaluated the antiproliferative activity of the ethanol extract of artificially cultured AC (EEAC) on breast cancer cells (T47D cells) in vivo and in vitro. Ethanol extract of artificially cultured AC inhibited T47D cells’ proliferation mediated by cell cycle arrest at G1 phase as well induced autophagy. Immunoblotting assay confirmed that EEAC not only decreased the expression of the cell-cycle-related proteins but also increased the expression of transcription factor FOXO1, autophagic marker LC3 II, and p62. Ethanol extract of artificially cultured AC mediated endoplasmic reticulum stress by promoting the expression of IRE1 (inositol-requiring enzyme 1α), GRP78/Bip (glucose regulating protein 78), and CHOP (C/EBP homologous protein). Apart from previous studies, HDACs (histone deacetylases) activity was inhibited as demonstrated by a cell-free system, immunoblotting, and immunofluorescence assays following EEAC treatment. The in vivo studies demonstrated that EEAC decreased tumor volume and inhibited tumor growth without any significant side effects. High performance liquid chromatography profile demonstrated similar triterpenoids compared to the profile of wild AC ethanol extract. The multiple targets of EEAC on breast cancer cells suggested that this extract may be developed as a potential dietary supplement targeting this debilitating disease.
Highlights
Breast cancer is the second leading cause of cancer-associated mortalities among woman in developed eastern and western countries [1,2]
There are three types of breast cancer including estrogen receptor (ER) positive cancer, human epidermal growth factor two positive (HER2) cancer as well as triple negative breast cancer (TNBC) which is negative for ER, PR, and HER2 [3]
T, h24e%im, 2m2u%n,oaflnudo5r1e%scernecdeurcetisounlt,srefusprtehcetirvceolyn.fiTrhmeeudstehoaft EEEEAACC ((5500 μμgg//mmLL) )reinsuhlitbeidtedin HmDoAreCrseadcuticvtiiotynroesfuHltDinAgCin1th(5e6a%ce),tyHlaDtiAonCo2f h(2is9t%on),eHs HD3AaCnd3 H(346%(F)i,gaunrde 4HCD; FAigCu4re(4S81%). )Tahsessehorewsunltisn iFnidgiucareted4Bt.hTatheEEimACmumnoodfluuloarteesdceenpciegerneestuicltss tfhurrotuhgerh cthonefiinrmhiebdititohnatofEEHADCAC(5s0aμctgiv/mityL)minedhiibatiteedd hHisDtoAnCe sacaecttyivlaittiyonre. sulting in the acetylation of histones H3 and H4 (Figure 4C; Figure S1). These results indicated that extract of artificially cultured AC (EEAC) modulated epigenetics through the inhibition of histone deacetylases (HDAC) activity mediated histone acetylation
Summary
Breast cancer is the second leading cause of cancer-associated mortalities among woman in developed eastern and western countries [1,2]. Other molecular targets were studied in the war against cancer including endoplasmic reticulum (ER), which is an essential cellular organelle that maintains cellular function and proliferation It is the center of proteins synthesis, folding, and quality control [13]. When tested against breast cancer cells, AC extract inhibited COX-2 expression in MDA-MB-231 cells and activated caspase-3 in MCF-7 cells as well as it induced DNA damage in T47D cells resulting in MCcFe-l7luclealrls aapsowpetollsaiss i[t23in–d25u]c.eAdnDtrNodAiadcaimnnaagmeoimneTa4a7nDdceitlsls arectsiuvletincogninsticteulelunltasrwapeoreptsousbisje[c2t3e–d25to]. Sulting in the acetylation of histones H3 and H4 (Figure 4C; Figure S1) These results indicated that EEAC modulated epigenetics through the inhibition of HDACs activity mediated histone acetylation. HPLPCLCprporfiolfeisleosfoAf CACmmajoarjotrrittreirteprepneoniodisdosfotfhtehethetahnaonlol ecoxeEtnxrEpetataxAhrctiaatrnCcraoemTtcfcdtroaowiotctfnehfoirltwledwapoieigsifnlnliraddceuomadiiffldtrreiatsuunhnmiaigtedtirinaebsntgjhaoogcemodrbrnbiaoetesoprdsimidediteaueeisanetrrijespdaocdnereaEdnftntEfhroedEeiAcitEdtemCEsArsE[paCw3cjAeo5oen]rwCm.roaeHeicprwdetPeaivsLvereareCecveloducapmolearutmvtoopaefaptdaitellhorued(nesaFde(otiwFnegftitdugAoislurdCot(erhFfeAm6eiAgA6CawCuAj,oBr,iewrBel)xd.)tht.r6OriiAOActauehCcu,rrBtpar.re)erer.xeTnestOohsrureuieadulsltctpsrsrsteoo.srssnfhTehustoshhoilubwteweslleteeressetddfhhsosatuorthnhwlioatoatsswttledsEehEdtoAhwtaChteadt EEthAEaCEt AEcCEoAucolCdntcaboienuelcddontbhseeidcsoaemnresedidmaeasrjeoodrntaresitoeorfnpteehnoeofiadthlstecroanmltaeptriavnreaedtsivotoeutrshcoeeuswrcoiledfsAAoCfCAetxChtartathceat.ftfTehfcfeteirvcetesilvuyletlsryesdhreoudwcueescdetsutmumoror grgorwtohtwahttEahEnaAdnCdexceohxuihblditbbsietascnoaannnsaitdni-etriue-tdmuaomsrooignreiegnoeifcntiehcfefeeafclftteecirntnaivntiivveoivswoouiwtrhcieotshuootfuaAtnCayntshyiagstniegiffinfecicfaitncivatenslyitdsreieddeeuffceeefcsftet.uctm. or growth and exhibits an anti-tumorigenic effect in vivo without any significant side effect
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