Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2017

Open Access 01-12-2017 | Research article

The inhibitory effects of compound Muniziqi granule against B16 cells and harmine induced autophagy and apoptosis by inhibiting Akt/mTOR pathway

Authors: Nan Zou, Yue Wei, Fenghua Li, Yang Yang, Xuemei Cheng, Changhong Wang

Published in: BMC Complementary Medicine and Therapies | Issue 1/2017

Login to get access

Abstract

Background

Compound Muniziqi granule (MNZQ) is a multi-component herbal preparation and a popular traditional Uighur medicine used in China for treating endocrine disorder-induced acne, chloasma, dysmenorrhea, menopausal syndrome, and melanoma. Harmine presented in MNZQ has been confirmed potential anticancer effect on the B16 cells among others. The purpose of this study is to explore the inhibitory effects of MNZQ against B16 cells and mechanism of autophagy and apoptosis induced by harmine in B16 cells.

Methods

The cell viability was calculated by CCK8 assay. The in vitro tyrosinase activity was determined by spectrophotometry. The harmine-induced autophagy was demonstrated by electron microscopy and MDC staining. Flow cytometry was used to measure cell death and cell cycle distribution. All proteins expression was assessed by western blot.

Results

MNZQ and some herb extracts contained in preparation displayed inhibitory effects on B16 cells but without inhibition on mushroom tyrosinase compared with kojic acid. The formation of autophagosome was markedly induced by harmine with the accretion of LC3-II and the degeneration of p62 in B16 cells, which indicated that harmine was an autophagy inducer. Cell death and sub-G2 population suggested that harmine could induce cell death. Particularly, 3-MA, an autophagy inhibitor, was discovered to prevent harmine-induced decrease of the cell viability and cell cycle arrest on G2 phase, indicating that autophagy was vital to the cell death. In addition, the results indicated that harmine could inhibit the phosphorylation of Akt and mTOR, which might mediate autophagy.

Conclusion

Harmine could induce autophagy and apoptosis by inhibiting Akt/mTOR pathway in B16 cells. Harmine might be a promising therapeutic agent for treatment of melanoma in MNZQ.
Literature
1.
2.
Chan K. Chinese medicinal materials and their interface with Western medical concepts. J Ethnopharmacol. 2005;96:1–18.CrossRefPubMed
3.
Chinese Pharmacopoeia Committee, Drug Standards of the Ministry of Public Health of the People’s Republic of China (Uygur Pharmaceutical Section). Chinese Pharmacopoeia Committee, 1998. China, pp 80.
4.
Cheng JJ, Ma TY, Liu W, Wang HX, Jiang JZ, Wei Y, Tian HM, Zou N, Zhu YD, Shi HL, Cheng XM, Wang CH. In in vivo evaluation of the anti-inflammatory and analgesic activities of compound Muniziqi granule in experimental animal models. BMC Complem Altern M. 2016; https://​doi.​org/​10.​1186/​s12906-016-0999-y.
5.
Alqathama A, Prieto JM. Natural products with therapeutic potential in melanoma metastasis. Nat Prod Rep. 2015;32:1170–82.CrossRefPubMed
6.
Ye Y, Chou GX, Mu DD, Wang H, Chu JH, Leung AKM, Fong WF, Yu ZP. Screening of chinese herbal medicines for antityrosinase activity in a cell free system and B16 cells. J Ethnopharmacol. 2010;129:387–90.CrossRefPubMed
7.
8.
Li TY, Kon N, Jiang L, Tan MJ, Ludwig T, Zhao YM, Baer R, Gu W. Tumor suppression in the absence of p53-mediated cellcycle arrest, apoptosis, and senescence. Cell. 2012;149:1269–83.CrossRefPubMedPubMedCentral
9.
Lin CY, Wu HY, Wang PL, Yuan CJ. Mammalian Ste20-like protein kinase 3 induces a caspase-independent apoptotic pathway. Int J Biochem Cell Biol. 2010;42:98–105.CrossRefPubMed
10.
Cheng Y, Qiu F, Ye YC, Tashiro S, Onodera S, Ikejima T. Oridonin induces G2/M arrest and apoptosis via activating ERK-p53 apoptotic pathway and inhibiting PTK-Ras-Raf-JNK survival pathway in murine fibrosarcoma L929 cells. Arch Biochem Biophys. 2009;490:70–5.CrossRefPubMed
11.
Yun J, Afaq F, Khan N, Mukhtar H. Delphinidin, an anthocyanidin in pigmented fruits and vegetables, induces apoptosis and cell cycle arrest in human colon cancer HCT 116 cells. Mol Carcinog. 2009;48:260–70.CrossRefPubMedPubMedCentral
12.
Eom HJ, Choi J. P38 MAPK activation, DNA damage, cell cycle arrest and apoptosis as mechanisms of toxicity of silver nanoparticles in jurkat T cells. Environ Sci Technol. 2010;44:8337–42.CrossRefPubMed
13.
14.
Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy and apoptosis in prostate cancer stem cells via PI3K/Akt/mTOR signaling pathway. Cancer Lett. 2013;343:179–89.CrossRefPubMed
15.
16.
Herassandoval D, Pérezrojas JM, Hernándezdamián J, Pedrazachaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal. 2014;26:2694–701.CrossRef
17.
Li SP, Cheng XM, Wang CH. A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum. J Ethnopharmacol. 2017;203:127–62.CrossRefPubMed
18.
Lamchouri F, Settaf A, Cherrah Y, Zemzami M, Lyoussi B, Zaid A, Atif N, Hassar M. Antitumour principles from Peganum Harmala seeds. Therapie. 1999;54:753–8.PubMed
19.
Chen Q, Chao RH, Chen HS, Hou XR, Yan HF, Zhou SF, Peng WL, Xu AL. Antitumor and neurotoxic effects of novel harmine derivatives and structure-activity relationship analysis. Int J Cancer. 2004;114:675–82.CrossRef
20.
Zhang H, Sun K, Ding J, Xu H, Zhu L, Zhang K, Li XL, Sun WH. Harmine induces apoptosis and inhibits tumor cell proliferation, migration and invasion through down-regulation of cyclooxygenase-2 expression in gastric cancer. Phytopharmacology. 2014;21:348–55.
21.
22.
Hamsa TP, Kuttan G. Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro. Eur J Pharmacol. 2010;649:64–73.CrossRefPubMed
23.
Abe A, Yamada H, Moriya S, Miyazawa K. The β-carboline alkaloid harmol induces cell death via autophagy but not apoptosis in human non-small cell lung cancer A549 cells. Biol Pharm Bull. 2011;34:1264–72.CrossRefPubMed
24.
Chan YY, Kim KH, Cheah SH. Inhibitory effects of sargassum polycystum on tyrosinase activity and melanin formation in B16F10 murine melanoma cells. J Ethnopharmacol. 2011;137:1183–8.CrossRefPubMed
25.
Mizushima N. Methods for monitoring autophagy. Int J Biochem Cell B. 2004;36:2491–502.CrossRef
26.
27.
Tran AT, Ramalinga M, Kedir H, Clarke R, Kumar D. Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells. Eur J Nutr. 2015;54:265–72.CrossRefPubMed
28.
Xie ZG, Xie Y, Xu YJ, Zhou HB, Xu W, Dong QR. Bafilomycin A1 inhibits autophagy and induces apoptosis in MG63 osteosarcoma cells. Mol Med Rep. 2014;10:1103–7.PubMed
29.
Climstein M, Furness J, Hing W, Walsh J. Lifetime prevalence of non-melanoma and melanoma skin cancer in australian recreational and competitive surfers. Photodermatol Photo. 2016;32:207–13.CrossRef
30.
Ivanov VN, Bhoumik A, Ronai Z. Death receptors and melanoma resistance to apoptosis. Oncogene. 2003;22:3152–61.CrossRefPubMed
31.
Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Brit J Dermatol. 2012;166:1069–80.CrossRef
32.
Cao MR, Li Q, Liu ZL, Liu HH, Wang W, Liao XL, Pan YL, Jiang JW. Harmine induces apoptosis in HepG2 cells via mitochondrial signaling pathway. HBPD Int. 2011;10:599–604.PubMed
33.
Zhang P, Huang CR, Wang W, Zhang XK, Chen JJ, Wang JJ, Lin Jiang JW. Harmine hydrochloride triggers G2 phase arrest and apoptosis in MGC-803 cells and SMMC-7721 cells by upregulating p21, activating caspase-8/bid, and downregulating ERK/bad pathway. Phytother Res. 2015;30:31–40.CrossRefPubMed
34.
Wu M, Lao YZ, Xu NH, Wang XY, Tan HS, Fu WW, Lin ZX, Xu HX. Guttiferone k induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death. Phytomedicine. 2015;22:902–10.CrossRefPubMed
35.
Fan CD, Su H, Zhao J, Zhao BX, Zhang SL, Mao JT. A novel copper complex of salicylaldehyde pyrazole hydrazone induces apoptosis through up-regulating integrin β4 in H322 lung carcinoma cells. Eur J Med Chem. 2010;45:1438–46.CrossRefPubMed
36.
Shinojima N, Yokoyama T, Kondo Y, Kondo S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 2007;3:635–7.CrossRefPubMed
37.
Vucicevic L, Misirkic M, Janjetovic K, Vilimanovich U, Sudar E, Isenovic E, Prica M, Harhaji-Trajkovic T, Bumbasirevic V, Trajkovic V, Compound C. Induces protective autophagy in cancer cells through ampk inhibition-independent blockade of Akt/mTOR pathway. Autophagy. 2011;7:40–50.CrossRefPubMed
38.
Surviladze Z, Sterk RT, Deharo SA, Ozbun MA. Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-kinase/AKT/mTOR pathway and inhibition of autophagy. J Virol. 2013;87:2508–17.CrossRefPubMedPubMedCentral
39.
Wu YT, Tan HL, Huang Q, Ong CN, Shen HM. Activation of the PI3K-AkT-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy. Autophagy. 2009;5:824–34.CrossRefPubMed
40.
Li C, Wang Y, Wang C, Yi X, Li M, He X. Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells. Phytomedicine. 2017;28:10–8.CrossRefPubMed
Metadata
Title
The inhibitory effects of compound Muniziqi granule against B16 cells and harmine induced autophagy and apoptosis by inhibiting Akt/mTOR pathway
Authors
Nan Zou
Yue Wei
Fenghua Li
Yang Yang
Xuemei Cheng
Changhong Wang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2017
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-017-2017-4

Other articles of this Issue 1/2017

BMC Complementary Medicine and Therapies 1/2017 Go to the issue

Research article

The functional property of royal jelly 10-hydroxy-2-decenoic acid as a melanogenesis inhibitor

Research article

Modified lingguizhugan decoction incorporated with dietary restriction and exercise ameliorates hyperglycemia, hyperlipidemia and hypertension in a rat model of the metabolic syndrome

Research article

Cutaneous neurogenic inflammation in the sensitized acupoints induced by gastric mucosal injury in rats

Research article

Chemical composition and some biological activities of the essential oils from basil Ocimum different cultivars

Research article

Methanol leaves extract Hibiscus micranthus Linn exhibited antibacterial and wound healing activities

Research article

Participation trends in holistic movement practices: a 10-year comparison of yoga/Pilates and t’ai chi/qigong use among a national sample of 195,926 Australians