The currently available chemotherapeutic regimens against gastric cancer are not very effective, leading to high recurrence and poor survival. Resveratrol is a naturally occurring polyphenol with potent apoptosis-inducing activity. However, the mechanism underlying its actions remains unknown. In the present study, human gastric adenocarcinoma SGC7901 cells were treated with resveratrol (0, 25, 50, 100 and 200 ╬╝mol/L) for 48 h, and cellular apoptosis DNA damage were determined. In certain experiments, cells were incubated with superoxide dismutase (100 U/mL), catalase (300 U/mL) or sirtinol (10 ╬╝mol/L) to determine the role of reactive oxygen species (ROS) and sirtuin1 in resveratrol-induced cellular apoptosis. Treatment with resveratrol (50-200 ╬╝mol/L) for 48 h significantly induced apoptosis and DNA damage in human gastric cancer SGC7901 cells. This was due to the increased generation of ROS following resveratrol treatment because incubation of cells with superoxide dismutase (100 U/mL) or catalase (300 U/mL) attenuated resveratrol-induced cellular apoptosis. Interestingly, treatment with resveratrol (25-200 ╬╝mol/L) did not affect the level and activity of sirtuin1, whereas the sirtuin1 inhibitor sirtinol (10 ╬╝mol/L) significantly reduced sirtuin1 activity. Furthermore, treatment with sirtinol (10 ╬╝mol/L) did not have any effect on apoptosis induced by resveratrol. These data provide evidence that resveratrol induces apoptosis via ROS, but independent of sirtuin1, in the human gastric cancer cell line SGC7901.
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.
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┬▒0.25 and 2.00┬▒0.25, 0.80┬▒0.08 and 1.50┬▒0.28, 1.25┬▒0.06 and 1.25┬▒0.05, and 5.00┬▒0.22 and 4.50┬▒0.14mg/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.
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.
Treatment of gastric cancer remains a major challenge, and new anticancer drugs are urgently required. This study investigated whether dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, could inhibit the growth of gastric cancer both in vitro and in vivo. A series of in vitro experiments including MTT, colony-forming, wound healing, invasion, cell cycle, cellular senescence, and apoptosis assays were performed to examine the antiproliferative and antimetastatic effects of DHA on three gastric cancer cell lines, SGC-7901, BGC823, and MGC803. The result showed that the proliferation rate and colony-forming abilities of gastric cancercells were significantly suppressed by DHA together with significant suppression of the expressions of proliferation markers (PCNA, cyclin E, and cyclin D1), and upregulation of p21 and p27.
Moreover, DHA induced cellular senescence, G1 phase cell cycle arrest and hindered the migration and invasion of gastric cancer cells corresponding with downregulation of MMP-9 and MMP-2. Furthermore, DHA significantly induced apoptosis through suppressing Bcl-2 as well as activating caspase-9 and PARP. Treatment of gastric cancer cells with DHA increased miR-15b and miR-16 expression, caused a downregulation of Bcl-2, resulting in apoptosis of gastric cancer cells. In vivo, our data showed that DHA significantly inhibited the growth of SGC7901 cell-transplanted tumors. In summary, we have shown that DHA is able to inhibit the growth and metastasis of human gastric cancer. The modulation of miR-15b and miR-16 mediated the apoptosis effects of DHA in gastric cancer cells. Our work suggested that DHA has significant anticancer effects against gastric cancer both in vivo and in vitro, indicating that it is a promising therapy for human gastric cancer.
Tratamentele chemoterapice disponibile ├«n mod curent ├«mpotriva cancerului gastric nu sunt foarte eficiente, duc├ónd la recidive ┼či slab─â supravie┼úuire. Resveratrolul este un polifenol ap─ârut pe cale natural─â cu puternic─â ac┼úiune de inducere a apoptozei. Cu toate acestea mecanismele care stau la baza ac┼úiunilor sale r─âm├ón necunoscute. ├Än studiul prezent celule ale adenocarcinomului uman gastric SGC7901au fost tratate cu resveratrol (0,25, 50, 100 ┼či 200 ┬Ámol/L) pentru 48 de ore, ┼či a fost determinat─â distrugerea ADN-ului prin apoptoz─â celular─â. ├Än anumite experimente unele celule au fost incubate cu superoxid dismutaz─â (100 U/ml), catalaz─â (300 U/ml) sau sirtinol (10 ┬Ámol/L) pentru a determina rolul speciilor de oxigen reactive (ROS) ┼či a sirtuinei1 ├«n apoptoza celular─â indus─â de resveratrol. Tratamentul cu resveratrol (50-200 ┬Ámol/L) timp de 48 de ore a indus semnificativ apoptoza ┼či distrugerea ADN-ului la celulele de cancer uman gastric SGC7901. Aceasta a fost datorit─â genera┼úiilor m─ârite de ROS care au urmat tratamentului cu resveratrol, deoarece incuba┼úia celulelor cu superoxid distutaz─â (100 U/ml) sau catalaz─â (300 U/ml) a atenuat apoptoza celular─â indus─â de resveratrol. ├Än mod interesant, tratamentul cu resveratrol (25-200 ┬Ámol/L) nu a afectat nivelul ┼či activitatea sirtuinei1, ├«n timp ce inhibitorul de sirtuin─â1, sirtinol (10 ┬Ámol/L), a redus semnificativ activitatea sirtuinei1. Mai mult, tratamentul cu sirtinol (10 ┬Ámol/L) nu a avut nici un efect asupra apoptozei indus─â de resveratrol. Aceste date furnizeaz─â probe c─â resveratrolul induce apoptoza via ROS, dar independent de sirtuina1, la linia celular─â a cancerului gastric uman SGC7901.
Tratamentul cancerului gastric r─âm├óne o provocare major─â, ┼či se impune g─âsirea unor noi medicamente anti-cancer c├ót mai cur├ónd posibil. Acest studiu investigheaz─â faptul dac─â dihidroartemisininul (DHA), un derivat semi-sintetic al artemisininului, poate inhiba dezvoltarea cancerului gastric at├ót in vivo c├ót ┼či in vitro. Au fost desf─â┼čurate o serie de experimente in vitro, incluz├ónd MTT, formarea de colonii, vindecarea unor r─âni, invazie, ciclu celular, ├«mb─âtr├ónire celular─â ┼či teste de apoptoz─â, pentru a examina efectele anti-proliferative ┼či anti-metastatice ale DHA asupra a trei linii celulare ale cancerului gastric, SGC-7901, BGC823 ┼či MGC803. Rezultatele au ar─âtat c─â rata de proliferare ┼či abilitatea de a forma colonii ale celulelor canceroase gastrice au fost semnificativ supresate de DHA odat─â cu o supresare semnificativ─â a expresiei markerilor de proliferare (PCNA, ciclina E ┼či ciclina D1) ┼či hiperreglarea lui p21 ┼či p27.
Mai mult dec├ót at├ót, DHA a indus senescen┼ú─â celular─â, stoparea ciclului celular ├«n faza G1 ┼či a ├«mpiedicat migra┼úia ┼či invazia celulelor canceroase gastrice cu hiporeglarea lui MMP-9 ┼či MMP-2. ├Än plus, DHA a indus semnificativ apoptoza prin supresarea Bcl-2 ca ┼či prin activarea caspazei 9 ┼či PARP. Tratamentul celulelor gastrice cu DHA a crescut expresia miR-15b ┼či miR-16 ┼či a cauzat o hiporeglare a Bcl-2, rezult├ónd apoptoza celulelor canceroase gastrice. In vivo datele noastre au ar─âtat c─â DHA a inhibat semnificativ tumorile cu celule SGC7901, transplantate. ├Än rezumat am ar─âtat c─â DHA este capabil s─â inhibe dezvoltarea ┼či metastazele cancerului gastric uman. Modularea miR-15b ┼či miR-16 a mediat efectele de apoptoz─â ale DHA ├«n celulele canceroase gastrice. Munca noastr─â sugereaz─â c─â DHA are efecte semnificative anti-cancer asupra cancerului gastric at├ót in vivo c├ót ┼či in vitro, indic├óndu-l ca pe un tratament promi┼ú─âtor pentru cancerul gastric la oameni.