PART Ⅱ： The Anti-tumor Effects Of Verbascoside From Cistanche
Mar 10, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
Hasan Alaa Aldeen Khalaf1, Ruaa Azziz Jasim1, Ismail Taha Ibrahim
Abstract:
Cancer is a set of diseases including abnormal growth of cells that can spread to another tissue. Verbascoside from cistanche (or acteoside) is a naturally occurring, water-soluble secondary metabolite with significant biological properties, which is distributed widely in the plant kingdom. Verbascoside from cistanche is a pharmacologically active compound with much recent evidence that supports its biological activities and safety. This review focuses on the recent studies that are concerned with the antitumor activities of Verbascoside from cistanche alone and as a synergistic agent as well as nanoproduct. It also shows the latest advances in its antitumor effects, cytotoxic selectivity, and its efficiencies in treating cancer, in vitro and/or Vivo.
Keywords: Verbascoside from cistanche, Phenylethanoids, Phenylpropanoids, Glycosides, Cytotoxic, Antitumor
3.6 Hematologic Cancer
The dynamics of hematopoietic stem cells may precede many blood cancers, involving myelodysplastic syndrome, myeloproliferative neoplasms, chronic lymphocytic leukemia, and acute myeloid leukemia [56]. Kyung-Won Lee and his group revealed that VERB prevented the growth of HL-60 cells (human leukemia cell line) in a time and concentration-dependent style with an IC50 of 30 mM. Additionally, flow cytometric analysis revealed that VERB blocked progression of the cell cycle at the G1 phase in HL-60 cell [57]
Nanotechnology is the use of material on an atomic, molecular, or supramolecular scale for different purposes. Medicinally, nanotechnology plays an advanced role in enhancing the absorption, bioavailability, and efficacy of drugs [58]. It has been shown that nanocarriers loaded with antioxidants can be used in various formulations with a high and controlled-release antioxidant effect that would meet the modern requests of consumers [11]. Recently, Chinese scientists developed a new system for better delivery of VERB for enhancing its chemo-therapeutic effect against the drug-resistant type of leukemia cells (K562/A02, KA). A novel combination product of poly isopropyl acrylamide with gold nano- shells, showed a better role of drug delivery [59]. VERB nanoproduct (200 mm) showed obvious tumor inhibitory effects by increasing the expression of initiator caspases (e.g. caspase 3,8,9) inside the KA cells with the smaller size of the tumor in comparison with the control group and those treated with VERB alone, and the result proved that this delivery system enhances the anticancer activity of VERB [60].
3.7 Skin Cancer
Polyphenols of plant origin, are known for their antioxidant, anti-inflammatory, antimutagenic, and antiproliferative characteristics in vitro and in vivo [61]. Protective effects of polyphenols in green tea against UVB-induced skin cancer [62], procyanidins in grape seeds [63], curcumin, silymarin, and genistein were confirmed to be potent protective agents against initiation and progression steps of UVA and UVB carcinogenesis on the mouse model [64] [65] [66] [67]. However- er, because of their poor gastrointestinal absorption, little bioavailability, and enhanced metabolism; the clinical chemoprotective worth of VERB and other polyphenols through the oral route is still questioned [68] pared to C5N cells, as well as, VERB resulted in suppression of the MMP-2 and MMP-9 activities in the A5 cells. This indicates that VERB has evidenced selectivity toward tumor cells [69].
3.8 Prostate Cancer
Prostate cancer is one of the most common carcinomas in men [70]. There are many chemotherapeutic agents for treating prostate cancer, which is extremely toxic to the normal tissues [71]. To resolve this problem, co-therapy of a chemotherapeutic agent with a remedy possessed an anti-proliferative effect. Several studies have revealed that natural secondary metabolites that have a cinnamic acid moiety possess anti-proliferative effects on tumor cell lines [57].
VERB has the ability to promote rat prostate apoptosis and inhibit benign prostatic hyperplasia (BPH). VERB with high-dose treatment can result in apoptosis in the rat prostate cells, which is significantly higher in comparison with the model group [72]. Treatment with VERB significantly prevented cell proliferation, and migration capabilities of men's prostate tumor cell line (e.g. PC-3 cells and Du-145) by suppression of HMGB1/RAGE pathway, which resulted in downregulation of TGF-β-associated epithelial-mesenchymal transition (EMT) progression [73].
4 Miscellaneous
DNA is under continuous stress, which results from cellular metabolism or environmental factors [74]. Reactive oxygen species (ROS) cause DNA damage through oxidative damage, hence, playing an important role in the initiation of tumors [75]. The oxidative DNA stress has been implicated in the induction of several diseases including inflammation, heart disease, and cancer [76]. Abeliophyllum distich um (AAD) is a Korean plant that is rich in VERB [77]. A recent Korean study clarified the essential role of AAD in preventing the oxidative damage of DNA. The results showed that AAD eliminated 1,1-Diphenyl-2-picryl hydroxyl (DPPT) and 2,2-Azino-bis (3-ethylbenzene-6-sulfonic acid) diammonium salt (ABTS) free radicals in a dose-dependent manner, IC 50 for AAD and control (L ascorbic acid) were 8.8 and 5.0 μg/ml respectively in the case of DPPT, and 6.47 and 10.49 μg/ml, respectively, in case of ABTS. ADD also enhanced the cell viability compared with control cells after exposure to H2O2-induced damage [78].
VERB is considered as strongest antioxidant recognized in Australian olive mill waste [79]. VERB Hydroxytyrosol and oleuropein at 10 μM significantly de- creased the proliferation of gastric adenocarcinoma (AGS cells) by 19, 27, and 16%, respectively. Though, the ethyl acetate extract of olive mill waste (bisphenols extract) was more potent as anti-proliferative than VERB alone [80].
VERB also showed antitumor activity against oral squamous cell carcinoma (OSCC) by decreasing the vitality and metastasis of HN6 and HN4 cancer cells, while stimulating apoptosis. VERB efficiently inhibited activation and downstream of nuclear factor (NF)-jB and expression of Bcl-2/Bcl-XL, resulting in the high rate of OSCC cell apoptosis, consequently, mRNA and matrix metalloproteinase-9 expression has been suppressed, thus, VERB inhibiting metastasis of cancer cells [81].
4.1 VERB and Nanotechnology
Based on the advantage of nanotechnology in cancer therapeutics in improving the pharmacokinetics and reducing the systemic toxicities of chemotherapies assuming the selective targeting and delivery of these anticancer drugs to tumor tissues [82]. So the beneficial effect of medicinal agent-loaded nanoparticles has become highly concluded [83]. Many types of research study the application of VEBR loaded nanoparticles in the treatment of cancer and the results were better than without nanoparticles. VERB carried on nickel nanoparticles showed a synergistic effect on apoptosis induction in a doxorubicin-resistant human erythro- leukemic cell line (K562). Observations demonstrate that nickel has the ability to facilitate the VERB uptake into K562 cells. Additionally, in vivo study indicated that the tumor growth in the mice could be efficiently inhibited by these nano- particles. Thus, VERB-Nickel can serve as a novel approach to sensitively lead the tumor cells to effective chemotherapy [77]. VERB carried on gold nanoparticles (Au) also were studied and demonstrated that VERB-Au nanoparticles provided an effective strategy to control tumor cell growth [29].
4.2 Safety and Side Effects of VERB
VERB has a wide range of biological and pharmacological activities so studying its side effects and toxicity is important. [18]. VERB has an oral LD50 of less than 2000 mg/kg, which gives it a high level of safety [33]. A single intraperitoneal VERB injection at 1, 2, and 5 g per kg did not induce deaths and side effects in mice. Therefore, the LD50 value of VERB was found to be greater than 5 g per kg, and a substance with an LD50 in the range of 1 - 5 g per kg is considered low-toxic [84]. Additionally, in vitro, VERB showed no cytotoxic effects on HepG2 and NIH cells at concentrations up to 400 μM, as well as, VERB did not cause significant changes in hematological and biochemical and histopathological parameters [85]. Further wide studies may be required to set up the possible adverse effects of VERB.
5 Conclusions
When used as a single treatment to 0.1875 μM when combined with 0.1 μM VERB. VERB + 5-Fu-treated cells, showed the lowest p-AKT levels, in comparison with VERB, control, and 5-Fu-treated cells.
Resistant cells are characterized by modified membrane transport, improved DNA repair, defects in the apoptotic pathway, modification of proteins, target molecules, and pathway mechanisms, like enzymatic deactivation [86]. One way to overcome the multidrug-resistant tumor cell is the nanoproduct, which enhances the bioavailability of anticancer agents inside the tumor cell. VERB nanoproduct significantly stimulated apoptosis-related caspases expression in tumor cells, which might offer a new chemotherapeutic approach in cancer treatment such as leukemia. ROS is like a sword with two edges, at low levels, ROS enhances the survival of tumor cells [87], while at a high level, ROS can overwhelm tumor growth by activation of cell cycle inhibitors [88]. Additionally, VERB has a high ability to increase ROS inside the tumor cell-like A549, HT-29, and MCF-7 that showed a time-dependent generation of ROS in tumor cells (1 - 24 hours) [49].
Collective data with the evidence showed that VERB is an active compound with high selectivity, no toxicity in animals, and no mutagenic effects and it seems to be possible for the future use of the co-therapy of VERB and chemotherapy in the clinic [69] [89]. Also, the loading of VERB on nanoparticles can provide a good tool for the delivery of VERB to cancer sites [9].
In spite of the fortune of laboratory data, which is accessible that describes the anti-tumor activities of VERB after in vitro results add to the animal models, many questions remain unsettled with respect to actual clinical applications. Evidence-based human researches on a large scale with precise therapeutic settings are important. More intensive studies are necessary to settle the clinical potential of VERB, thus permitting its acceptance as a therapeutic compound. VERB is also has a special structure that suggested an interesting scaffold with many reactive sites for combinatorial chemistry.
Conflicts of Interest: The authors declare no conflicts of interest regarding the publication of this paper.
References
[56]Lin, H.P., Jiang, S.S. and Chuu, C.P. (2012) Caffeic Acid Phenethyl Ester Causes p21Cip1 Induction, Akt Signaling Reduction, and Growth Inhibition in PC-3 Human Prostate Cancer Cells. PLoS ONE, 7, e31286. https://doi.org/10.1371/journal.pone.0031286
[57] Surendiran, A., Sandhiya, S., Pradhan, S.C. and Adithan, C. (2009) Novel Applications of Nanotechnology in Medicine. Indian Journal of Medical Research, 130, 689-701.
[58] Jiang, C., Li, H., Jia, X., Ma, X., Qian, Y. and Qian, W. (2010) Fabrication and Characterization of Poly (N-isopropyl acrylamide)-Gold Nanoshell Structures. Journal of Nanoscience and Nanotechnology, 10, 6599-605. https://doi.org/10.1166/jnn.2010.2540
[59] Ma, Z., Zhao, X., Jiang, C., Yu, J., Wu, J. and Zeng, X. (2016) Gold Nanoshells with Verbascoside Induce the Apoptosis of Drug-Resistant Leukemia Cells through Caspases Pathway and Inhibit Tumor Growth. Journal of Nanoscience and Nanotechnology, 16, 7118-7124. https://doi.org/10.1166/jnn.2016.11357
[60] Afaq, F. and Katiyar, S.K. (2011) Polyphenols: Skin Photoprotection and Inhibition of Photocarcinogenesis. Mini-Reviews in Medicinal Chemistry, 11, 1200-1215.
[61] Wang, Z.Y., Agarwal, R., Bickers, D.R. and Mukhtar H. (1991) Protection against Ultraviolet B Radiation-Induced Photocarcinogenesis in Hairless Mice by Green Tea Polyphenols. Carcinogenesis, 12, 1527-1530. https://doi.org/10.1093/carcin/12.8.152
[62] Mittal, A., Elmets, C.A. and Katiyar, S.K. (2003) Dietary Feeding of Proanthocyanidins from Grape Seeds Prevents Photocarcinogenesis in SKH-1 Hairless Mice: Relationship to Decreased Fat and Lipid Peroxidation. Carcinogenesis, 24, 1379-1388. https://doi.org/10.1093/carcin/bgg095
[63] Wright, T.I., Spencer, J.M. and Flowers, F.P. (2006) Chemoprevention of Nonmelanoma Skin Cancer. Journal of the American Academy of Dermatology, 54, 933- 946. https://doi.org/10.1016/j.jaad.2005.08.062
[64] Aziz, M.H., Reagan-Shaw, S., Wu, J., Longley, B.J. and Ahmad, N. (2005) Chemoprevention of Skin Cancer by Grape Constituent Resveratrol: Relevance to Human Disease? The FASEB Journal, 19, 1193-1195. https://doi.org/10.1096/fj.04-3582fje
[65] Katiyar, S.K. (2007) UV-Induced Immune Suppression and Photocarcinogenesis: Chemoprevention by Dietary Botanical Agents. Cancer letters, 255, 1-11. https://doi.org/10.1016/j.canlet.2007.02.010
[66] Korkina, L.G., De Luca, C., Kostyuk, V.A. and Pastore, S. (2009) Plant Polyphenols and Tumors: From Mechanisms to Therapies, Prevention, and Protection against Toxicity of Anti-Cancer Treatments. Current Medicinal Chemistry, 16, 3943-3965.
[67] Nichols, J.A. and Katiyar, S.K. (2010) Skin Photoprotection by Natural Polyphenols: Anti-Inflammatory, Antioxidant and DNA Repair Mechanisms. Archives of Dermatological Research, 302, 71-83. https://doi.org/10.1007/s00403-009-1001-3
[68] Cheimonidi, C., Samara, P., Polychronopoulos, P., Tsakiri, E.N., Nikou, T., Myrianthopoulos, V., Sakellaropoulos, T., Zoumpourlis, V., Mikros, E., Papassideri, I., Argyropoulou, A. (2018) Selective Cytotoxicity of the Herbal Substance Acteoside against Tumor Cells and Its Mechanistic Insights. Redox Biology, 16, 169-178. https://doi.org/10.1016/j.redox.2018.02.015
[69] Abate-Shen, C. and Shen, M.M. (2002) Mouse Models of Prostate Carcinogenesis. Trends in Genetics, 18, S1-S5. https://doi.org/10.1016/S0168-9525(02)02683-5
[70] Van Bokhoven, A., Varella-Garcia, M., Korch, C., Johannes, W.U, Smith, E.E., Miller, H.L., Nordeen, S.K., Miller, G.J. and Lucia, M.S. (2003) Molecular Characterization of Human Prostate Carcinoma Cell Lines. The Prostate, 57, 205-225. https://doi.org/10.1002/pros.10290
[71] Sun, W.D., Chen, F. and Sun, Y. (2008) The Pharmacological Research of Acteoside
on the Action Inhibited Begin Prostatic Hyperplasia in Rats. Journal of Yangzhou University (Agricultural and Life Science Edition), Issue 4, 33-36.
[72] Wu, C.H., Chen, C.H., Hsieh, P.F., Lee, Y.H., Kuo, W.W. and Wu, R.C. (2021) Verbascoside Inhibits the Epithelial-Mesenchymal Transition of Prostate Cancer Cells through High-Mobility Group Box 1/Receptor for Advanced Glycation End- Products/TGF-β Pathway. Environmental Toxicology, 36, 1080-1089. https://doi.org/10.1002/tox.23107
[73] Schärer, O.D. (2003) Chemistry and Biology of DNA Repair. Angewandte Chemie International Edition, 42, 2946-2974. https://doi.org/10.1002/anie.200200523
[74] Han, H.M., Kwon, Y.S. and Kim, M.J. (2016) Antioxidant and Antiproliferative Activity of Extracts from Water Chestnut (Trapa japonica Flow). Korean Journal of Medicinal Crop Science, 24, 14-20. https://doi.org/10.7783/KJMCS.2016.24.1.14
[75] Gilgun-Sherki, Y., Rosenbaum, Z., Melamed, E. and Offen, D. (2002) Antioxidant Therapy in Acute Central Nervous System Injury: Current State. Pharmacological Reviews, 54, 271-284. https://doi.org/10.1124/pr.54.2.271
[76] Park, J., Xi, H., Han, J., Lee, J., and Kim, Y. (2020) Prediction and Identification of Biochemical Pathway of Acteoside from Whole Genome Sequences of Abeliophyl- lum Distichum Nakai, Cultivar Ok Hwang 1ho. Journal of Convergence for Information Technology, 10, 76-91. https://doi.org/10.22156/CS4SMB.2020.10.03.076
[77] Jang, T.W., Choi, J.S. and Park, J.H. (2020) Protective and Inhibitory Effects of Acteoside from Abeliophyllum Distichum Nakai against oxidative DNA damage. Molecular Medicine Reports, 22, 2076-2084. https://doi.org/10.3892/mmr.2020.11258
[78] Obied, H.K., Prenzler, P.D. and Robards, K. (2008) Potent Antioxidant Biophenols from Olive Mill Waste. Food Chemistry, 111, 171-178. https://doi.org/10.1016/j.foodchem.2008.03.058
[79] Konczak, I., Obied, H.K., Prenzler, P.D., Rehman, A.U. and Robards, K. (2009) Chemistry and Bioactivity of Olive Biophenols in Some Antioxidant and Antiproliferative in Vitro Bioassays. Chemical Research in Toxicology, 22, 227-234. https://doi.org/10.1021/tx8004168
[80] Zhang, Y., Yuan, Y., Wu, H., Xie, Z., Wu, Y., Song, X., Wang, J., Shu, W., Xu, J., Liu, B. and Wan, L. (2018) Effect of Verbascoside on Apoptosis and Metastasis in Human Oral Squamous Cell Carcinoma. International Journal of Cancer, 143, 980- 991. https://doi.org/10.1002/ijc.31378
[81] Sindhwani, S., and Chan, W.C. (2021) Nanotechnology for Modern Medicine: Next Step towards Clinical Translation. Journal of Internal Medicine, 289, 1-136. https://doi.org/10.1111/joim.13254
[82] Sim, S. and Wong, N.K. (2021) Nanotechnology and Its Use in imaging and Drug Delivery (Review). Biomedical Reports, 14, Article No. 42. https://doi.org/10.3892/br.2021.1418
[83] Hayes, A.W. and Loomis, T.A. (1996) Loomis’s Essentials of Toxicology. Elsevier, Amsterdam.
[84] Etemad, L., Zafari, R., Vahdati-Mashhadian, N., Adel Moallem, S., Shirvan, Z.O. and Hosseinzadeh, H. (2015) Acute, Sub-Acute and Cell Toxicity of Verbascoside. Research Journal of Medicinal Plant, 9, 354-360. https://doi.org/10.3923/rjmp.2015.354.360
[85] Alfarouk, K.O., Stock, C.M., Taylor. S., Walsh, M., Muddathir, A.K., Verduzco, D., Bashir, A.H., Mohammed, O.Y., Elhassan, G.O., Harguindey, S. and Reshkin, S.J. (2015) Resistance to Cancer Chemotherapy: Failure in Drug Response from ADME to P-GP. Cancer Cell International, 15, Article No. 71. https://doi.org/10.1186/s12935-015-0221-1
[86] Irani, K., Xia, Y., Zweier, J.L., Sollott, S.J., Der, C.J. and Fearon, E.R. (1997) Mitogenic Signaling Mediated by Oxidants in Ras-transformed Fibroblasts. Science, 275, 1649-1652. https://doi.org/10.1126/science.275.5306.1649
[87] Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S.I., and Tahara, H. (2006) Mitogenic Signalling and the p16 INK4a-Rb Pathway Cooperate to Enforce Irreversible Cellular Senescence. Nature Cell Biology, 8, 1291-1297. https://doi.org/10.1038/ncb1491
[88]Lu, B., Li, M., Zhou, F., Huang, W., Jiang, Y., Mao, S., Zhao, Y., and Lou, T. (2016) The Osmanthus fragrance Flower Phenylethanoid Glycoside-Rich Extract: Acute and Subchronic Toxicity Studies. Journal of Ethnopharmacology, 187, 205-212. https://doi.org/10.1016/j.jep.2016.04.049
