SH003 as a Therapeutic Anticancer Agent
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers14041089

SH003, a novel herbal medicine containing Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii, showed the potential to act as an anticancer agent in previous research studies.

anticancer agent cancer natural compound phytochemical herbal medicine

1. Introduction

There are many types of cancer treatments, including chemotherapy, radiotherapy, surgery, hormone therapy, immunotherapy, etc. [1]. A single or combination therapy can be applied depending on the type of cancer; among the therapies, chemotherapy is one of the most common treatments to kill cancer cells and to stop them from growing rapidly [2]. Despite the favor of chemotherapies, such therapies have led to numerous side effects, drug resistance and inadequate target specificity [2]. Thus, there has been a significant interest in finding natural anticancer agents. Developing natural-product-based drugs may take longer than traditional cancer drugs; natural-product-based drugs are known to overcome the harmful effects of chemotherapies and possess the strengths to target various cancer types. On the negative side, the quality control of the undiscovered active components and sources of natural compounds may be challenging.

Herbal medicines have also shown potential in reducing side effects while improving the immune system [3]. In particular, Chinese herbal medicine (CHM) has long been used to prevent and treat cancer in China. Huang et al. mentioned that arsenic trioxide, a toxic Chinese medicine, has been successfully applied in the clinical treatment of patients with acute promyelocytic leukemia; moreover, some formulae, including PHY906 based on Huang-Qin-Tang, have indicated a synergic effect with conventional drugs for improving the life quality of patients [4].

2. Characteristics of SH003

SH003 is a mixture of Huang-Qi (Astragalus membranaceus; AG), Dang-Gui (Angelica gigas; AM), and Gua-Lou-Gen (Trichosanthes Kirilowii; TK), which are traditionally used in East Asian medicine. According to the theory of traditional medicine, the effect of Huang-Qi is to tonify qi, the effect of Dang-Gui is to tonify blood, and the effect of Gua-Lou-Gen is to disperse swelling and expel pus [5]. SH003 extracts were provided by HANPOONG (HANPOONG PHARM & FOODS Co., Jeonju, Korea), which followed good manufacturing practice (GMP) procedures. In brief, Astragalus membranaceus (333 g), Angelica gigas (333 g), and Trichosanthes kirilowii Maximowicz (333 g) were mixed at a 1:1:1 ratio and then extracted with 10 times the volume of 30% ethanol at 100 °C for 3 h. This process was performed 2 times. The extract was dried at reduced pressure (40 Torr) at 60 °C for 18 h. Notably, the experimental study proved that Danggwibohyeoltang, a mixture of AM and AG, inhibits the immune-enhancing effect [6].  As shown in Figure 1, the anti-cancer effect of SH003 has been demonstrated by several publications.
Cancers 14 01089 g001 550
Figure 1. The timeline of SH003 (BC: breast cancer; PC: pancreatic cancer; CaP: prostate cancer; CC: cervical cancer; GC: gastric cancer, CIPN: chemotherapy-induced peripheral neuropathy and NSCLC: non-small cell lung cancer).

3. Current Advances of SH003 in Tumor Suppression

Herbal medicines have been used to prevent or inhibit tumor growth and metastasis. SH003 plays a crucial role in regulating various types of cancer (Figure 2 and Table 1).
Cancers 14 01089 g002 550
Figure 2. A mechanistic summary of SH003.
Table 1. A summary of the effects of SH003 on cancer, immune system and chemotherapy-related side effects.
Table
Cancer Type Cell Type Proposed Effects Methods Mechanism Refs.
Breast cancer MDA-MB-231 Suppression of tumor growth and metastasis in vitro
(0–500 μg/mL)
in vivo
(500 mg/kg)		 Inhibition STAT3-IL-6 Signaling [7]
MDA-MB-231 and HCC-38 Pro-apoptosis and autophagy induction in vitro
(0–500 μg/mL)
in vivo
(10, 100, 500 mg/kg)		 Accumulation p62 in autolysosomes [8]
Hs578T, MDA-MB-231, ZR-75-1, MCF7 and T47D Pro-apoptosis, synergistic anticancer effect with paclitaxel in vitro
(0–200 μg/mL)		 Increase in p73 expression [9]
MDA-MB-231 Pro-apoptosis, synergistic anticancer effect with doxorubicin in vitro
(0–500 μg/mL)
in vivo
(500 mg/kg)		 Caspase cascade activation [10]
Paclitaxel-resistant breast cancer cell (MCF-7/PAX) Overcoming drug resistance in vitro
(0–500 μg/mL)		 Inhibition of MDR1 activity, inhibition of STAT3 signaling pathway [11][12]
Endothelial cells Human umbilical vein endothelial cells (HUVECs) Anti-angiogenesis in vitro
(0–50 μg/mL)
in vivo
(2 mg/kg)		 Blockade VEGF binding to VEGFR2 [13]
Prostate cancer DU145 Pro-apoptosis in vitro
(0–500 μg/mL)		 Inhibition ERK signaling pathway [14]
Cervical cancer HeLa Pro-apoptosis in vitro
(0–500 μg/mL)		 G1 cell cycle arrest, ROS generation [15]
Gastric cancer AGS and SNU-638 Autophagic cell death in vitro
(0–400 μg/mL)		 ER stress induction and inhibition of STAT3-G9a axis [16]
Non-Small Cell Lung Cancer H460 Synergistic anticancer effect with docetaxel in vitro
(0–500 μg/mL)
in vivo
(557.569 mg/kg)		 Inhibition EGFR–STAT3 signaling pathway [17]
C57BL/6 Mice Docetaxel-Induced Neuropathy Mouse Model Alleviation of docetaxel-induced neuropathic pain in vivo
(557.569 mg/kg)		 Inhibition of proinflammatory cytokines (TNF-α and IL-6), NF-κB and STAT3 [18]
Immune cell Macrophage (RAW 264.7) and NK cell Immune-enhancing activity in vitro
(0–500 μg/mL)
in vivo
(400 mg/kg)		 Production immunostimulatory cytokines and NO, activation of NF-κB [19]

3.1. Breast Cancer

In 2014, it reported taht the tumor-suppressive effect of SH003 on triple-negative breast cancer [7]. It was shown that SH003 inhibits tumor growth and metastasis to the lung in the mouse xenograft model via the down-regulation of vascular endothelial cell marker (CD31). From in vitro results, SH003 inhibited the growth of various breast cancer cell lines, including luminal A, luminal B, HER2, and TNBC subgroups, when compared with the normal epithelial cell. Moreover, treatment with SH003 inhibited migration, invasion, and the anchorage-dependent colony formation of MDA-MB-231 TNBC cell lines. Western blot analysis revealed that SH003 decreased the expression of STAT3 phosphorylation and STAT3-dependent proteins. Meanwhile, SH003 also blocked the nuclear translocation of phosphorylation and the transcriptional activities of STAT3 in MDA-MB-231 cells. By inhibiting STAT3 activation, SH003 decreased the production of STAT3-mediated IL-6. Evidence showed for the first time that SH003 could be a novel anti-cancer herbal mixture for TNBC by inhibiting the STAT3-IL-6 autocrine loop. Another study was performed to define the growth-inhibitory effect of SH003 on p53-mutant TNBC [9]. SH003 has a significant anti-cancer effect via p73-mediated apoptosis in TNBC cells with p53 mutation.

3.2. Lung Cancer

According to microscopic features, lung cancer is classified into non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) [20][21]. NSCLC patients commonly receive platinum or taxane-based regimens or targeted therapy for epidermal growth factor receptor (EGFR) [22][23]. Docetaxel—taxane with anti-mitotic properties—is an effective anti-cancer agent, causing cell cycle arrest and apoptosis in NSCLC [24][25][26]. However, docetaxel-mediated chemoresistance and severe side effects, including peripheral neuropathy, anorexia, and cachexia, are still the cause of treatment failure in cancer patients [27][28]. Recent studies have focused on the development of novel treatment strategies by combining chemotherapy with herbal medicines for NSCLC treatment [29][30]. Several clinical studies demonstrated the survival benefit of chemotherapy in combination with traditional Chinese herbal medicines in cancer patients [31][32][33]. The results of an MTT cell viability assay showed that the co-treatment of SH003 and docetaxel synergistically inhibited the viability of NSCLC A549 and H460 cell lines. 

3.3. Other Malignancies

Besides breast and lung cancer, the anti-cancer effects of SH003 on other cancer types have been investigated by non-clinical studies [14][15][16]. In 2016, Choi et al. investigated the anti-cancer effects of SH003 in prostate cancer cells [14]. SH003 treatment dose-dependently inhibited the viability of prostate cancer DU145 cell lines by inducing apoptosis. Moreover, SH003 induced apoptotic cell death via inhibiting the ERK signaling pathway, while ERK overexpression reversed it. In the case of cervical cancer, Lee et al. demonstrated that SH003 exhibits an anti-cancer effect by regulating cell cycle arrest and apoptotic cell death [15]. Kim et al. reported the effect of SH003 on the autophagic death of gastric cancer cells [16]. In gastric cancer, SH003 treatment dose- and time-dependently inhibited the viability of various gastric cancer cell lines, the inhibition of which was associated with the induction of apoptosis. Meanwhile, SH003 also induced ER stress via PERK-ATF4-CHOP signaling, inhibiting G9a by suppressing STAT3 phosphorylation and activating autophagy. Of note, SH003-induced ER stress induced BNIP3-related autophagic death via the suppression of STAT3/G9a axis under hypoxic conditions.

3.4. Tumor Angiogenesis

Tumor angiogenesis is crucial for tumor growth and distant metastasis [34][35]. The inhibition of tumor angiogenesis has been considered a potential target for cancer treatment. Vascular endothelial cell growth factor (VEGF) released from cancer cells binds to VEGF receptor (VEGFR) on vascular endothelial cells, resulting in neo-angiogenesis. Based on the finding that SH003 suppressed TNBC tumor growth with the down-regulation of endothelial cell marker (CD31) in a mouse xenograft model [7], Choi et al. performed a further study to prove an anti-angiogenic effect of SH003 [13]. While VEGF induced the migration, invasion, and tube formation of human vascular endothelial cells (HUVEC), SH003 treatment inhibited it.

3.5. Managing Cancer-Related Adverse Effect

3.5.1. Chemotherapy-Induced Peripheral Neuropathy

Lee et al. demonstrated that SH003 alleviated mechanical allodynia in the docetaxel-induced mouse CIPN model. Intravenous docetaxel injection induced the degeneration of intraepidermal nerve fibers in the feet of C57BL/6 mice, but SH003 treatment alleviated it. Additionally, SH003 decreased the upregulation of TNF- α and IL-6 in plasma and increased expression of phospho-NF-κB and phospho-STAT in L4-L6 spinal cord and sciatic nerves in docetaxel-injected mice. Based on these findings, therapeutic indications of SH003 can be expanded to CIPN in addition to killing cancer.

3.5.2. Immune-Enhancing Effect

The immune system of cancer patients who receive several therapies, including chemotherapy and radiotherapy, is commonly weakened, resulting in tumor progression and poor prognosis [36][37]. Several studies reported that herbal medicines and their derivatives exhibit immunostimulatory effects [38][39]. Han et al. demonstrated that SH003 improves immunosuppression via the activation of immune cells such as macrophages, splenocytes, and NK cells [19]. SH003 treatment increased the production of colony-stimulating factors, IL-2, IL-6, IL-12, TNF-α, nitric oxide, and iNOS. Moreover, the transcription factor NF-κB was enhanced by SH003. In splenocytes, SH003 also stimulated the production of IFN-γ, IL-2, IL-12, TNF-α, and nitric oxide. The splenic lymphocyte proliferation and splenic NK cell activity were increased by SH003 treatment.

3.6. Anti-Cancer Effect of SH003 Derivatives

Since SH003 is a herbal mixture that contains multiple phytochemicals, it was necessary to decipher what compounds of SH003 show anti-cancer effects. From 2012 to 2020, the SH003 research group has found apigenin, cucurbitacin D, decursin, kaempferol, and quercetin as potential anti-cancer agents (Table 2). In brief, a number of studies have demonstrated that each putative active compound mainly regulates the signaling pathways in apoptosis or autophagy, which are the key anticancer targets of SH003. Therefore, SH003 is expected to have anticancer effects through the synergistic effect of these compounds, although non-clinical studies should prove this. Moreover, the previous research focused on the chemical profiling of SH003 identified several constituents, whereas the anticancer effect of single components and their combination are still unknown [8]. However, there are still undiscovered active components in SH003. Thus, further studies should be performed to identify new compounds in SH003 and to investigate the synergistic interactions of multiple components.
Table 2. A summary of SH003 derivative-induced effects on cancer treatment.
Table
Herb Active Compound Cancer Type/Cell Type Mechanism Refs.
Astragalus membranaceus, Trichosanthes Kirilowii Maxim. Apigenin
(0–40 μM [40])
(0–100 μM [41][42])		 Breast cancer (MCF-7. SK-BR-3, BT-474, MDA-MB-453, MCF-7 HER-2 and MCF7/ADR) Inhibition of STAT3 and NFκB signaling, downregulation of MDR1 expression [40][41][42]
Astragalus membranaceus, Trichosanthes Kirilowii Maxim. Quercetin
(0–100 μM)		 Breast cancer (BT-474) Apoptosis through inhibition of STAT3 [43]
Astragalus membranaceus Kaempferol
(0–100 μM)		 Gastric cancer (AGS, SNU-216, NCI-N87, SNU-638, and MKN-74) Activaiton of IRE1-JNK-CHOP pathway, G9a inhibition [44]
Trichosanthes Kirilowii Maxim. Cucurbitacin D
(0–2 μg/mL [45])
(0–10 μM [46])
(0–0.8 μM [47])		 Doxorubicin-resistant human breast carcinoma (MCF7/ADR) Inhibition of STAT3 and NFκB signaling [45]
Non-small-cell lung cancer (H1299, HCC827 and HCC827GR) ErbB3 and EGFR signaling inhibition, synergistic effect with CDDP/PXD, overcoming gefitinib resistance [46]
Pancreatic cancer (Capan-1) G2/M phase arrest through ROS-p38 pathway [47]
Angelica gigas Nakai Decursin
(0–50 μg/mL)		 Doxorubicin-resistant human breast carcinoma (MCF7/ADR) Inhibition of P-glycoprotein expression [44]

References

  1. Cancers Home Page. Available online: https://www.cancer.gov/about-cancer/treatment/types (accessed on 28 January 2022).
  2. Aung, T.N.; Qu, Z.; Kortschak, R.D.; Adelson, D.L. Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action. Int. J. Mol. Sci. 2017, 18, 656.
  3. Wang, S.; Long, S.; Wu, W. Application of Traditional Chinese Medicines as Personalized Therapy in Human Cancers. Am. J. Chin. Med. 2018, 46, 953–970.
  4. Huang, M.Y.; Zhang, L.L.; Ding, J.; Lu, J.J. Anticancer drug discovery from Chinese medicinal herbs. Chin. Med. 2018, 13, 35.
  5. National College of Korean Medicine Publication Committee on Joint Textbook. Herbology; Younglimsa: Seoul, Korea, 2016.
  6. Kim, M.C.; Lee, G.H.; Kim, S.J.; Chung, W.S.; Kim, S.S.; Ko, S.G.; Um, J.Y. Immune-enhancing effect of Danggwibohyeoltang, an extract from Astragali Radix and Angelicae gigantis Radix, in vitro and in vivo. Immunopharmacol. Immunotoxicol. 2012, 34, 66–73.
  7. Choi, Y.K.; Cho, S.G.; Woo, S.M.; Yun, Y.J.; Park, S.; Shin, Y.C.; Ko, S.G. Herbal extract SH003 suppresses tumor growth and metastasis of MDA-MB-231 breast cancer cells by inhibiting STAT3-IL-6 signaling. Mediat. Inflamm. 2014, 2014, 492173.
  8. Choi, Y.K.; Cho, S.G.; Choi, Y.J.; Yun, Y.J.; Lee, K.M.; Lee, K.; Yoo, H.H.; Shin, Y.C.; Ko, S.G. SH003 suppresses breast cancer growth by accumulating p62 in autolysosomes. Oncotarget 2017, 8, 88386–88400.
  9. Choi, E.K.; Kim, S.M.; Hong, S.W.; Moon, J.H.; Shin, J.S.; Kim, J.H.; Hwang, I.Y.; Jung, S.A.; Lee, D.H.; Lee, E.Y.; et al. SH003 selectively induces p73dependent apoptosis in triplenegative breast cancer cells. Mol. Med. Rep. 2016, 14, 3955–3960.
  10. Woo, S.M.; Kim, A.J.; Choi, Y.K.; Shin, Y.C.; Cho, S.G.; Ko, S.G. Synergistic Effect of SH003 and Doxorubicin in Triple-negative Breast Cancer. Phytother. Res. PTR 2016, 30, 1817–1823.
  11. Choi, H.S.; Cho, S.G.; Kim, M.K.; Lee, H.J.; Moon, S.H.; Jang, H.J.; Ko, S.G. SH003 enhances paclitaxel chemosensitivity in MCF-7/PAX breast cancer cells through inhibition of MDR1 activity. Mol. Cell. Biochem. 2017, 426, 1–8.
  12. Seo, H.S.; Ku, J.M.; Lee, H.J.; Woo, J.K.; Cheon, C.; Kim, M.; Jang, B.H.; Shin, Y.C.; Ko, S.G. SH003 reverses drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer cells. Biosci. Rep. 2017, 37, BSR20170125.
  13. Choi, H.S.; Kim, M.K.; Lee, K.; Lee, K.M.; Choi, Y.K.; Shin, Y.C.; Cho, S.G.; Ko, S.G. SH003 represses tumor angiogenesis by blocking VEGF binding to VEGFR2. Oncotarget 2016, 7, 32969–32979.
  14. Choi, Y.J.; Choi, Y.K.; Lee, K.M.; Cho, S.G.; Kang, S.Y.; Ko, S.G. SH003 induces apoptosis of DU145 prostate cancer cells by inhibiting ERK-involved pathway. BMC Complement. Altern. Med. 2016, 16, 507.
  15. Lee, K.M.; Lee, K.; Choi, Y.K.; Choi, Y.J.; Seo, H.S.; Ko, S.G. SH003induced G1 phase cell cycle arrest induces apoptosis in HeLa cervical cancer cells. Mol. Med. Rep. 2017, 16, 8237–8244.
  16. Kim, T.W.; Cheon, C.; Ko, S.G. SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells. Cell Death Dis. 2020, 11, 717.
  17. Jeong, M.S.; Lee, K.W.; Choi, Y.J.; Kim, Y.G.; Hwang, H.H.; Lee, S.Y.; Jung, S.E.; Park, S.A.; Lee, J.H.; Joo, Y.J.; et al. Synergistic Antitumor Activity of SH003 and Docetaxel via EGFR Signaling Inhibition in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2021, 22, 8405.
  18. Lee, K.; Ku, J.M.; Choi, Y.J.; Hwang, H.H.; Jeong, M.; Kim, Y.G.; Kim, M.J.; Ko, S.G. Herbal Prescription SH003 Alleviates Docetaxel-Induced Neuropathic Pain in C57BL/6 Mice. Evid.-Based Complement. Altern. Med. eCAM 2021, 2021, 4120334.
  19. Han, N.R.; Kim, K.C.; Kim, J.S.; Ko, S.G.; Park, H.J.; Moon, P.D. The immune-enhancing effects of a mixture of Astragalus membranaceus (Fisch.) Bunge, Angelica gigas Nakai, and Trichosanthes Kirilowii (Maxim.) or its active constituent nodakenin. J. Ethnopharmacol. 2022, 285, 114893.
  20. Kriegsmann, M.; Haag, C.; Weis, C.A.; Steinbuss, G.; Warth, A.; Zgorzelski, C.; Muley, T.; Winter, H.; Eichhorn, M.E.; Eichhorn, F.; et al. Deep Learning for the Classification of Small-Cell and Non-Small-Cell Lung Cancer. Cancers 2020, 12, 1604.
  21. Zheng, M. Classification and Pathology of Lung Cancer. Surg. Oncol. Clin. N. Am. 2016, 25, 447–468.
  22. Chu, Q.; Vincent, M.; Logan, D.; Mackay, J.A.; Evans, W.K.; Lung Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-base Care. Taxanes as first-line therapy for advanced non-small cell lung cancer: A systematic review and practice guideline. Lung Cancer 2005, 50, 355–374.
  23. Hildebrandt, M.A.; Gu, J.; Wu, X. Pharmacogenomics of platinum-based chemotherapy in NSCLC. Expert Opin. Drug Metab. Toxicol. 2009, 5, 745–755.
  24. Herbst, R.S.; Khuri, F.R. Mode of action of docetaxel—A basis for combination with novel anticancer agents. Cancer Treat. Rev. 2003, 29, 407–415.
  25. Xiao, H.; Verdier-Pinard, P.; Fernandez-Fuentes, N.; Burd, B.; Angeletti, R.; Fiser, A.; Horwitz, S.B.; Orr, G.A. Insights into the mechanism of microtubule stabilization by Taxol. Proc. Natl. Acad. Sci. USA 2006, 103, 10166–10173.
  26. He, X.; Wang, J.; Li, Y. Efficacy and safety of docetaxel for advanced non-small-cell lung cancer: A meta-analysis of Phase III randomized controlled trials. OncoTargets Ther. 2015, 8, 2023–2031.
  27. d’Amato, T.A.; Landreneau, R.J.; McKenna, R.J.; Santos, R.S.; Parker, R.J. Prevalence of in vitro extreme chemotherapy resistance in resected nonsmall-cell lung cancer. Ann. Thorac. Surg. 2006, 81, 440–446, discussion in 446–447.
  28. Baker, J.; Ajani, J.; Scotte, F.; Winther, D.; Martin, M.; Aapro, M.S.; von Minckwitz, G. Docetaxel-related side effects and their management. Eur. J. Oncol. Nurs. 2009, 13, 49–59.
  29. Wu, J.; Liu, Y.; Fang, C.; Zhao, L.; Lin, L.; Lu, L. Traditional Chinese Medicine Preparation Combined Therapy May Improve Chemotherapy Efficacy: A Systematic Review and Meta-Analysis. Evid.-Based Complement. Altern. Med. eCAM 2019, 2019, 5015824.
  30. Cassileth, B.R.; Rizvi, N.; Deng, G.; Yeung, K.S.; Vickers, A.; Guillen, S.; Woo, D.; Coleton, M.; Kris, M.G. Safety and pharmacokinetic trial of docetaxel plus an Astragalus-based herbal formula for non-small cell lung cancer patients. Cancer Chemother. Pharmacol. 2009, 65, 67–71.
  31. Zhao, L.; Zhao, A.G.; Zhao, G.; Xu, Y.; Zhu, X.H.; Cao, N.D.; Zheng, J.; Yang, J.K.; Xu, J.H. Survival benefit of traditional chinese herbal medicine (a herbal formula for invigorating spleen) in gastric cancer patients with peritoneal metastasis. Evid.-Based Complement. Altern. Med. eCAM 2014, 2014, 625493.
  32. Lee, Y.C.; Chen, Y.H.; Huang, Y.C.; Lee, Y.F.; Tsai, M.Y. Effectiveness of Combined Treatment with Traditional Chinese Medicine and Western Medicine on the Prognosis of Patients with Breast Cancer. J. Altern. Complement. Med. 2020, 26, 833–840.
  33. Tang, W.R.; Yang, S.H.; Yu, C.T.; Wang, C.C.; Huang, S.T.; Huang, T.H.; Chiang, M.C.; Chang, Y.C. Long-Term Effectiveness of Combined Treatment with Traditional Chinese Medicine and Western Medicine on the Prognosis of Patients with Lung Cancer. J. Altern. Complement. Med. 2016, 22, 212–222.
  34. De Palma, M.; Biziato, D.; Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 2017, 17, 457–474.
  35. Teleanu, R.I.; Chircov, C.; Grumezescu, A.M.; Teleanu, D.M. Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment. J. Clin. Med. 2019, 9, 84.
  36. Florea, A.M.; Busselberg, D. Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers 2011, 3, 1351–1371.
  37. Ohm, J.E.; Carbone, D.P. Immune dysfunction in cancer patients. Oncology 2002, 16, 11–18.
  38. Wang, S.; Long, S.; Deng, Z.; Wu, W. Positive Role of Chinese Herbal Medicine in Cancer Immune Regulation. Am. J. Chin. Med. 2020, 48, 1577–1592.
  39. Wang, Y.; Zhang, Q.; Chen, Y.; Liang, C.L.; Liu, H.; Qiu, F.; Dai, Z. Antitumor effects of immunity-enhancing traditional Chinese medicine. Biomed. Pharmacother. 2020, 121, 109570.
  40. Seo, H.S.; Choi, H.S.; Kim, S.R.; Choi, Y.K.; Woo, S.M.; Shin, I.; Woo, J.K.; Park, S.Y.; Shin, Y.C.; Ko, S.G. Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFkappaB signaling in HER2-overexpressing breast cancer cells. Mol. Cell. Biochem. 2012, 366, 319–334.
  41. Seo, H.S.; Ku, J.M.; Choi, H.S.; Woo, J.K.; Jang, B.H.; Shin, Y.C.; Ko, S.G. Induction of caspase-dependent apoptosis by apigenin by inhibiting STAT3 signaling in HER2-overexpressing MDA-MB-453 breast cancer cells. Anticancer. Res. 2014, 34, 2869–2882.
  42. Seo, H.S.; Jo, J.K.; Ku, J.M.; Choi, H.S.; Choi, Y.K.; Woo, J.K.; Kim, H.I.; Kang, S.Y.; Lee, K.M.; Nam, K.W.; et al. Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells. Biosci. Rep. 2015, 35, e00276.
  43. Seo, H.S.; Ku, J.M.; Choi, H.S.; Choi, Y.K.; Woo, J.K.; Kim, M.; Kim, I.; Na, C.H.; Hur, H.; Jang, B.H.; et al. Quercetin induces caspase-dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in HER2-overexpressing BT-474 breast cancer cells. Oncol. Rep. 2016, 36, 31–42.
  44. Kim, T.W.; Lee, S.Y.; Kim, M.; Cheon, C.; Ko, S.G. Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis. 2018, 9, 875.
  45. Ku, J.M.; Kim, S.R.; Hong, S.H.; Choi, H.S.; Seo, H.S.; Shin, Y.C.; Ko, S.G. Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-kappaB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells. Mol. Cell. Biochem. 2015, 409, 33–43.
  46. Hong, S.H.; Ku, J.M.; Lim, Y.S.; Lee, S.Y.; Kim, J.H.; Cheon, C.; Ko, S.G. Cucurbitacin D Overcomes Gefitinib Resistance by Blocking EGF Binding to EGFR and Inducing Cell Death in NSCLCs. Front. Oncol. 2020, 10, 62.
  47. Kim, M.S.; Lee, K.; Ku, J.M.; Choi, Y.J.; Mok, K.; Kim, D.; Cheon, C.; Ko, S.G. Cucurbitacin D Induces G2/M Phase Arrest and Apoptosis via the ROS/p38 Pathway in Capan-1 Pancreatic Cancer Cell Line. Evid.-Based Complement. Altern. Med. eCAM 2020, 2020, 6571674.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Biochemistry & Molecular Biology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Chunhoo Cheon
View Times: 607
Revisions: 2 times (View History)
Update Date: 29 Mar 2022
Table of Contents
Video Production Service
Feedback