Anticancer potential of Hericium erinaceus extracts against human gastrointestinal cancers.

forr√°s: http://www.ncbi.nlm.nih.gov/pubmed/24631140


2014-04-15 12:36:18


Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Hericium is a genus of mushrooms (fungus) in the Hericiaceae family. Hericium erinaceus (HE) has been used for the treatment of digestive diseases for over 2000 years in China. HE possesses many beneficial functions such as anticancer, antiulcer, antiinflammation and antimicrobial effects, immunomodulation and other activities. The aim of the studies was to evaluate the anticancer efficacy of two extracts (HTJ5 and HTJ5A) from the culture broth of HE against three gastrointestinal cancers such as liver, colorectal and gastric cancers in both of in vitro of cancer cell lines and in vivo of tumor xenografts and discover the active compounds.

MATERIALS AND METHODS:

Two HE extracts (HTJ5 and HTJ5A) were used for the studies. For the study of chemical constituents, the HTJ5 and HTJ5A were separated using a combination of macroporous resin with silica gel, HW-40 and LH-20 chromatography then purified by semipreparative high-performance liquid chromatography (HPLC) and determined by nuclear magnetic resonance (NMR) spectra. For the in vitro cytotoxicity studies, HepG2 and Huh-7 liver, HT-29 colon, and NCI-87 gastric cancer cell lines were used and MTT assay was performed to determine the in vitro cytotoxicity. For in vivo antitumor efficacy and toxicity studies, tumor xenograft models of SCID mice bearing liver cancer HepG2 and Huh-7, colon cancer HT-29 and gastric cancer NCI-87 subcutaneously were used and the mice were treated with the vehicle control, HTJ5 and HTJ5A orally (500 and 1000mg/kg/day) and compared to 5-fluorouraci (5-FU) at the maximum tolerated dose (MTD, 25-30mg/kg/day) intraperitoneally daily for 5 days when the tumors reached about 180-200mg (mm(3)). Tumor volumes and body weight were measured daily during the first 10 days and 2-3 times a week thereafter to assess the tumor growth inhibition, tumor doubling time, partial and complete tumor response and toxicity.

RESULTS:

Twenty-two compounds were obtained from the fractions of HTJ5/HTJ5A including seven cycli dipeptides, five indole, pyrimidines, amino acids and derivative, three flavones, one anthraquinone, and six small aromatic compounds. HTJ5 and HTJ5A exhibited concentration-dependent cytotoxicity in vitro against liver cancer HepG2 and Huh-7, colon cancer HT-29, and gastric cancer NCI-87 cells with the IC50 in 2.50¬Ī0.25 and 2.00¬Ī0.25, 0.80¬Ī0.08 and 1.50¬Ī0.28, 1.25¬Ī0.06 and 1.25¬Ī0.05, and 5.00¬Ī0.22 and 4.50¬Ī0.14mg/ml; respectively. For in vivo tumor xenograft studies, HTJ5 and HTJ5A showed significantly antitumor efficacy against all four xenograft models of HepG2, Huh-7, HT-29 and NCI-87 without toxicity to the host. Furthermore, HTJ5 and HTJ5A are more effective than that of 5-FU against the four tumors with less toxicity.

CONCLUSION:

HE extracts (HTJ5 and HTJ5A) are active against liver cancer HepG2 and Huh-7, colon cancer HT-29 and gastric cancer NCI-87 cells in vitro and tumor xenografts bearing in SCID mice in vivo. They are more effective and less toxic compared to 5-FU in all four in vivo tumor models. The compounds have the potential for development into anticancer agents for the treatment of gastrointestinal cancer used alone and/or in combination with clinical used chemotherapeutic drugs. However, further studies are required to find out the active chemical constituents and understand the mechanism of action associated with the super in vivo anticancer efficacy. In addition, future studies are needed to confirm our preliminary results of in vivo synergistic antitumor efficacy in animal models of tumor xenografts with the combination of HE extracts and clinical used anticancer drugs such as 5-FU, cisplatin and doxurubicin for the treatment of gastrointestinal cancers.

 


Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin.

forr√°s: http://www.ncbi.nlm.nih.gov/pubmed/7750093


2014-03-11 14:21:47


Rapid cell death, as evidenced by a decrease in cell counts, was observed when molt-4-lymphoblastoid cells, a human leukemia cell line, were exposed to holotransferrin (12 microM) and dihydroartemisinin (1-200 microM). Incubation with either compound alone was significantly less effective. Significantly less cell death was observed when normal human lymphocytes were exposed to a combination of these 2 drugs. Probit analysis of doseresponse functions shows that the drug combination is approximately 100 times more effective on molt-4 cells than lymphocytes (LD50s for molt-4 and lymphocytes were 2.59 microM and 230 microM, respectively).

This drug combination may provide a novel approach for cancer treatment.


The anti-malarial artesunate is also active against cancer.

forr√°s: http://www.ncbi.nlm.nih.gov/pubmed/11251172


2014-03-11 13:52:27


Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua. ART reveals remarkable activity against otherwise multidrugresistant Plasmodium falciparum and P. vivax malaria.

ART has now been analyzed for its anti-cancer activity against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, USA. ART was most active against leukemia and colon cancer cell lines (mean GI50 values: 1.11+/-0.56 microM and 2.13+/-0.74 microM , respectively).

Nonsmall cell lung cancer cell lines showed the highest mean GI50 value (25.62+/-14.95 microM) indicating the lowest sensitivity towards ART in this test panel. Intermediate GI50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Importantly, a comparison of ART's cytotoxicity with those of other standard cytostatic drugs showed that ART was active in molar ranges comparable to those of established anti-tumor drugs. Furthermore, we tested CEM leukemia sub-lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea which do not belong to the N.C.I. screening panel. None of these drug-resistant cell lines showed cross resistance to ART. To gain insight into the molecular mechanisms of ART's cytotoxicity, we used a panel of isogenic Saccaromyces cerevisiae strains with defined genetic mutations in DNA repair, DNA checkpoint and cell proliferation genes. A yeast strain with a defective mitosis regulating BUB3 gene showed increased ART sensitivity and another strain with a defective proliferation-regulating CLN2 gene showed increased ART resistance over the wild-type strain, wt644. None of the other DNA repair or DNA check-point deficient isogenic strains were different from the wild-type. These results and the known low toxicity of ART are clues that ART may be a promising novel candidate for cancer chemotherapy.


Dihydroartemisinin improves the efficiency of chemotherapeutics in lung carcinomas in vivo and inhibits murine Lewis lung carcinoma cell line growth in vitro.

forr√°s: http://www.ncbi.nlm.nih.gov/pubmed/19756601


2014-03-11 13:38:18


PURPOSE:

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has exhibited thestrongest antimalarial activity among the derivatives of artemisinin. There is growingevidence that DHA has some impact against tumors. Our purpose was to evaluate in vitro antitumoral properties of DHA in the murine Lewis lung carcinoma (LLC) cell line. At thesame time, we observed the therapeutic effect of DHA combined with cyclophosphamide(CTX) in the LLC and combined with cisplatin (CDDP) in the human non-small cell lung cancer A549 xenotransplanted carcinoma in vivo.

METHODS:

Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromidemethod, apoptosis was measured by AO/EB double staining and flow cytometry. Theexpression of vascular endothelial growth factor (VEGF) receptor KDR/flk-1 was analyzed by western blotting and RT-PCR. In vivo activity of DHA combined with CTX or CDDP wasassayed through tumor growth and metastasis.

RESULTS:

Dihydroartemisinin exhibited high anti-cancer activity in LLC cell line. DHA also inducedapoptosis of LLC cells and influenced the expression of VEGF receptor KDR/flk-1.Furthermore, in both tumor xenografts, a greater degree of growth inhibition was achieved when DHA and chemotherapeutics were used in combination. The affection by DHA combined CTX on LLC tumor metastasis was significant.

CONCLUSIONS:

Dihydroartemisinin is a potent compound against LLC cell line in vitro. In vivo, thecombination strategy of DHA and chemotherapeutics holds promise for the treatment ofrelatively large and rapidly growing lung cancers.


A Hericium erinaceus [szak√°llas s√ľndiszn√≥ gomba, oroszl√°ns√∂r√©ny gomba, majomfej gomba] kivonatban rejlŇĎ r√°kellenes lehetŇĎs√©gek a hum√°n em√©sztŇĎrendszeri r√°kokkal szemben

forr√°s: http://www.ncbi.nlm.nih.gov/pubmed/24631140


2014-04-15 12:36:18


Kivonat

ETNOFARMAKOL√ďGIAI VONATKOZ√ĀS: A Hericium a gomb√°knak (fungus) egy nemzets√©ge a Hericiaceae csal√°dban. A Hericium erinaceus (HE)-t em√©sztŇĎrendszeri betegs√©gek kezel√©s√©re t√∂bb mint 2000 √©ve haszn√°lj√°k K√≠n√°ban. A HE sok olyan j√≥t√©kony hat√°ssal rendelkezik, mint amilyen p√©ld√°ul a r√°kelleness√©g, gyomorfek√©ly-elleness√©g, gyullad√°s g√°tl√°s √©s antimikrobi√°lis hat√°s, immunreakci√≥k befoly√°sol√°sa √©s egy√©b aktivit√°s. A vizsg√°latok c√©lja az volt, hogy √©rt√©kelj√ľk k√©t HE kult√ļra h√ļsleves t√°ptalajb√≥l t√∂rt√©nŇĎ kivonat√°nak (HTJ-5 √©s HTJ-5A) a r√°kkal szembeni hat√©konys√°g√°t h√°rom em√©sztŇĎrendszeri r√°k eset√©ben - mint amilyen a m√°j-, vastagb√©l- √©s gyomorr√°k ‚Äď , mind in vitro sejtvonalakon, mind pedig in vivo tumor xenograftokon (r√°ksejtbe√ľltet√©seken) √©s,  hogy felfedezz√ľk az akt√≠v vegy√ľleteket.

 

ANYAGOK √ČS M√ďDSZEREK: K√©t HE kivonatot (HTJ5 √©s HTJ5A) haszn√°ltunk a vizsg√°latokhoz. A k√©miai √∂sszetevŇĎk tanulm√°nyoz√°s√°hoz a HTJ5-√∂t √©s a HTJ5A-t  makropor√≥zus gyanta √©s szilikon g√©l kombin√°ci√≥j√°t alkalmazva HW 40 √©s LH 20 kromatogr√°fi√°val szepar√°ltuk, azt√°n megtiszt√≠tottuk szemipreparat√≠v, nagy teljes√≠tm√©nyŇĪ folyad√©k kromatogr√°fi√°val (high performance liquid chromatography - HPLC) szepar√°ltuk nukle√°ris m√°gneses rezonancia (NMR) spektrumokkal hat√°roztuk meg. Az in vitro citotoxicit√°si vizsg√°latokhoz HepG2 √©s Huh7 m√°j-, HT-29 vastagb√©l- √©s NCI-87 gyomorr√°k sejtvonalakat haszn√°ltunk √©s MTT pr√≥b√°t [egyfajta kolorimetri√°s pr√≥ba] v√©gezt√ľnk, hogy meghat√°rozzuk az in vitro citotoxicit√°st.

 

Az in vivo r√°kellenes hat√©konys√°gi √©s toxicit√°si vizsg√°latokhoz idegen r√°ksejt be√ľltet√©si modelleket alkalmaztunk s√ļlyos, kombin√°lt immunhi√°nyban (SCID) szenvedŇĎ egerekn√©l, bŇĎr al√° fecskendezve HepG2 √©s HUH-7 m√°jr√°k-, HT-29 vastagb√©lr√°k- √©s NCI-87 gyomorr√°k sejteket. Amikor a daganatok el√©rt√©k a k√∂r√ľlbel√ľl 180-200 mg-ot (mm3), az egereket 5 napon kereszt√ľl naponta sz√°jon √°t adagolt vivŇĎanyaggal, mint kontroll anyaggal, HTJ5-tel √©s HTJ5A-val (500 √©s 1000 mg/kg/nap) kezelt√ľk.  Ezt √∂sszehasonl√≠tottuk az ugyancsak 5 napon √°t naponta has√ľregbe (intraperitone√°lisan) maxim√°lisan toler√°lhat√≥ d√≥zisban (MTD ‚Äď maximum tolerated dose) adagolt ( 25-30 mg/kg/nap) 5-fluorouracil-lal (5-FU,  egy fajta antimetabolit). Ezt k√∂vetŇĎen az elsŇĎ t√≠z napban a daganatok t√©rfogat√°t √©s s√ļly√°t naponta, k√©sŇĎbb hetente 2-3-szor m√©rt√ľk, hogy √©rt√©kelj√ľk a daganatn√∂veked√©s g√°tol√°s√°t, a daganat megkettŇĎzŇĎd√©si idej√©t, a r√©szleges √©s teljes daganat v√°laszt √©s toxicit√°st.

 

EREDM√ČNYEK: A HTJ5/HTJ5A lep√°rl√°sokb√≥l huszonk√©t vegy√ľletet nyert√ľnk, bele√©rtve h√©t ciklikus kettŇĎs feh√©rj√©t, √∂t indolt, pirimidineket, aminosavakat √©s sz√°rmaz√©kaikat, h√°rom flavont, egy antrakinont √©s hat kis arom√°s vegy√ľletet. A HTJ5 √©s a HTJ5A koncentr√°ci√≥t√≥l f√ľggŇĎ citotoxicit√°st mutatott in vitro a  HepG2 √©s Huh-7 m√°jr√°k, a HT-29 vastagb√©l r√°k √©s az NCI-87 gyomorr√°k sejtekkel szemben a maxim√°lis g√°tl√≥ koncentr√°ci√≥ fel√©n√©l (IC50),  vonatkoz√≥an a 2,50¬Ī0,25 √©s a 2,00¬Īo,25; a 0,80¬Ī0,08 √©s az 1,50¬Ī0,28; az  1,25¬Ī0,06 √©s az 1,25¬Ī0,05;  valamint az 5,00¬Ī0,22 √©s 4,50¬Ī0,14 mg/ml-ben. Az in vivo idegen r√°kos sejt be√ľltet√©ses vizsg√°latokban a HTJ5 √©s a HTJ5A jelentŇĎs r√°kellenes hat√©konys√°got mutatott mind a n√©gy -  HepG2, Huh-7, HT-29 √©s NCI-87 -  idegen r√°kos sejt be√ľltet√©ses modell-lel szemben an√©lk√ľl, hogy m√©rgezŇĎ hat√°sa lett volna a gazda√°llatra. Ezen t√ļlmenŇĎen a HTJ5 √©s a HTJ5A kevesebb toxicit√°ssal hat√©konyabb volt a n√©gy r√°kt√≠pussal szemben, mint az 5-Fu.

 

K√ĖVETKEZTET√ČS: A HE kivonatok (HTJ5 √©s HTJ5A) akt√≠vak a HepG2 √©s Huh-7 m√°jr√°k-, a HT-29 vastagb√©lr√°k- √©s az NCI-87 gyomorr√°k sejtekkel szemben in vitro √©s az idegen r√°kos sejtekkel be√ľltetett SCID egerekn√©l in vivo. Mind a n√©gy in vivo daganat modell eset√©ben hat√©konyabbak √©s kev√©sb√© toxikusak az 5-FU-val √∂sszehasonl√≠tva. A vegy√ľletek magukban hordozz√°k annak a lehetŇĎs√©g√©t, hogy √∂n√°ll√≥an √©s/vagy a klinikailag alkalmazott kemoter√°pi√°s gy√≥gyszerekkel egy√ľtt r√°kellenes hat√≥anyagg√° fejlessz√©k ŇĎket. Azonban tov√°bbi vizsg√°latok sz√ľks√©gesek az akt√≠v vegyi √∂sszetevŇĎk megtal√°l√°s√°hoz √©s az erŇĎs in vivo r√°kellenes hat√©konys√°guk hat√°smechanizmus√°nak meg√©rt√©s√©hez. Tov√°bb√°, j√∂vŇĎbeni vizsg√°latok sz√ľks√©gesek ahhoz,  hogy megerŇĎs√≠t√©sre ker√ľljenek azok az elŇĎzetes, az idegen r√°kos sejt bejuttat√°sos √°llat k√≠s√©rletekn√©l kapott eredm√©nyek, ahol in vivo egy√ľtt hat√≥ r√°kellenes hat√©konys√°g mutatkozott,  amikor kombin√°l√°sra ker√ľltek az em√©sztŇĎszervi r√°kfajt√°k kezel√©s√©ben a HE kivonatok √©s az olyan klinikailag alkalmazott r√°kellenes gy√≥gyszerek, mint amilyen az 5-FU, cisplatin √©s a doxurubicin.


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