• Users Online: 306
  • Print this page
  • Email this page

 
Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 65  |  Issue : 1  |  Page : 12-20

Current research status of alkaloids against breast cancer


1 Oncology Hospital, General Hospital of Ningxia Medical University, Yinchua, Ningxia, China
2 Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China
3 Department of Pharmacology, College of Pharmacy, Ningxia Medical University; Key Laboratory of Ningxia Ethnomedicine Modernization, Ministry of Education, Ningxia Medical University; Ningxia Characteristic Traditional Chinese Medicine Modernization Engineering Technology Research Center, Yinchuan, Ningxia, China

Date of Submission22-Oct-2021
Date of Decision17-Dec-2021
Date of Acceptance05-Jan-2022
Date of Web Publication25-Feb-2022

Correspondence Address:
Dr. Ru Zhou
Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjp.cjp_89_21

Rights and Permissions
  Abstract 


Breast cancer is one of the most common malignant tumors in women worldwide. Surgery, chemotherapy, and targeted drugs are the main methods currently used in clinical treatment of breast cancer. Although they can improve the symptoms of patients, they are also accompanied by a large number of side effects. Because of its multiple targets, traditional Chinese medicine can improve the quality of life of breast cancer patients and reduce the side effects associated with chemotherapy, which plays an important role in the treatment of breast cancer. To a certain extent, traditional Chinese medicine has advantages that modern medicine does not have in the treatment of breast cancer. Alkaloids are active ingredients widely distributed in traditional Chinese medicine, which have a variety of pharmacological effects including anti-inflammatory, analgesic, and antitumor effects. The author reviewed the literature on the treatment of breast cancer with alkaloids extracted from traditional Chinese medicine in recent years, and discussed the unique advantages of alkaloids in the treatment of breast cancer.

Keywords: Alkaloid, breast cancer, Chinese medicine, mechanism, treatment


How to cite this article:
Hu Z, Pan J, Wang J, Pei Y, Zhou R. Current research status of alkaloids against breast cancer. Chin J Physiol 2022;65:12-20

How to cite this URL:
Hu Z, Pan J, Wang J, Pei Y, Zhou R. Current research status of alkaloids against breast cancer. Chin J Physiol [serial online] 2022 [cited 2022 Aug 17];65:12-20. Available from: https://www.cjphysiology.org/text.asp?2022/65/1/12/338442

Zhiqiang Hu and Jingling Pan contributed equally to this work.





  Introduction Top


Breast cancer is a malignant tumor that occurs in the glandular epithelium of breast tissue, which seriously threatens women's health. It is estimated that breast cancer accounts for 25% of all cancers in women.[1] The pathogenesis of breast cancer is mainly due to endocrine disorders. The breast is the target organ for a variety of endocrine hormones. Long-term abnormal stimulation of hormones can lead to excessive proliferation of breast cells and cancerous breast tissue.[2] Clinically, breast cancer is divided into three types according to the expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67: hormone receptor-positive breast cancer, epidermal growth factor receptor (EGFR) 2-positive breast cancer, and triple-negative breast cancer (TNBC).[3] For breast cancer patients, the first choice to control local tumor progression is surgical treatment and other traditional therapies include radiotherapy, chemotherapy, and endocrine therapy. For different types of breast cancer, a series of molecularly targeted drugs continue to emerge. Common targeted drugs include HER2-targeted drugs, such as trastuzumab and pertuzumab,[4] and human EGFR-targeted drugs, such as erlotinib and gefitinib.[5] Although significant progress has been made in treatment, local recurrence, distant metastasis, side effects, and drug resistance of anticancer drugs are the main causes of death in 80% of breast cancer patients.[6] Therefore, it has become a new trend to develop reliable and less toxic anticancer agents from natural sources.

Natural medicines are important resources for the development of antitumor drugs. Many alkaloids isolated from plants have attracted attention because of their outstanding antitumor activities, and >60% of cancer therapeutics on the market or in preclinical trials are based on natural products.[7] Many natural products, such as alkaloids, terpenes, coumarins, saponins, and polysaccharides, have been reported to have antitumor activity. Among the antitumor active substances that have been discovered, alkaloids account for a large proportion and have significant activity. A large number of studies have reported that alkaloids have been shown in the treatment of breast cancer due to their anti-proliferation, pro-apoptosis, and other pharmacological activities.[8] Based on the results of breast cancer research in vivo and in vitro, the author summarized the effects and mechanisms of alkaloid compounds in the treatment of breast cancer, aiming to provide a basis for deepening the understanding of breast cancer and provide a theoretical basis for clinical research.


  Definition of Alkaloids Top


Alkaloids are a type of nitrogen-containing basic organic compounds, most of which have complex ring structures, and nitrogen is mostly contained in the ring, which is one of the important active ingredients in Chinese medicine. Many anti-breast cancer drugs such as vinblastine, vinorelbine, and paclitaxel are natural alkaloids derived from Chinese medicine. Therefore, discovering new anti-breast cancer ingredients from Chinese medicine and conducting research on their effects and mechanisms provide a basis for innovative research on anti-breast cancer drugs [Table 1]. By consulting the literature, we identified a variety of alkaloid compounds that have significant inhibitory effects on breast cancer.
Table 1: Types of alkaloids for treatment of breast cancer

Click here to view



  The Effect and Mechanism of Alkaloids in the Treatment of Breast Cancer Top


Berberine

Berberine is a natural isoquinoline alkaloid compound found in many plants, which not only has anti inflammatory, immunomodulatory, and other pharmacological activities but also exerts a strong antitumor effect by inhibiting tumor cell proliferation, regulating cell cycle, and promoting apoptosis.[9],[10] Metadherin (MTDH) was believed to act as an oncogene, which enhanced the abilities of tumor cell invasion and migration, resulting in an aggressive phenotype and a poor prognosis; berberine could enhance apoptosis rates of breast cancer cells dependent on the regulation of MTDH.[11] Zhao et al. found that berberine activates the caspase-9-dependent apoptosis to inhibit the proliferation of triple-negative breast cancer cells.[12] Studies have also found that berberine can reverse breast cancer by inhibiting tumor cell growth and metastasis, and its mechanism is related to the regulation of the NLRP3 inflammasome pathway.[13] Although berberine helps inhibit tumor cell proliferation, high-dose administration is usually accompanied by side effects. Combination therapy can minimize drug resistance and side effects, and has been used in tumor treatment. The study found that the combination of theophylline and berberine suppresses MDA-MB-231 breast cancer cell proliferation, gene expression, and cell migration; the combination of berberine and evodiamine acts synergistically to suppress the proliferation of MCF-7 cells by inducing cell cycle arrest and apoptosis.[14],[15] Interestingly, in addition to being used as a therapeutic drug, berberine can also enhance breast cancer cells' response to chemotherapy drugs' sensitivity.[16],[17]

Paclitaxel

Paclitaxel, a diterpene alkaloid compound with anticancer activity, has been widely used clinically in the treatment of breast cancer, ovarian cancer, and some head-and-neck cancers and lung cancers.[18],[19] The remarkable biological activity and unique mechanism of action of paclitaxel make it a hot spot in anticancer research. Microtubules are an important component of the cytoskeleton of most eukaryotic organisms. They can not only maintain cell morphology and order internal structure of cells but also participate in cell movement, cell differentiation and development, and cell division and reproduction.[20] By binding to β-tubulin, paclitaxel affects the dynamic balance between α- and β-tubulin dimers and microtubules, promotes the assembly of tubulin into microtubules, and aggregates the assembled microtubules, which leads to cell arrest in G2 and M phases, abnormal or cessation of cell mitosis, and ultimately cell death. It indicates that paclitaxel may treat breast cancer by inducing cell apoptosis.[21]

Piperine

Piperine is an alkaloid with antitumor activity found in black pepper. Do et al. found that piperine can inhibit cell proliferation and induce cell apoptosis through caspase-3 activation and PARP cleavage. Overexpression of HER2 gene causes many types of cancer and has been shown to enhance cell proliferation, tumor growth, apoptosis resistance, angiogenesis, and metastasis, and piperine can inhibit HER2 gene expression at the transcriptional level.[22] In addition, piperine also inhibited survival-promoting Akt activation in TNBC cells, and inhibited survival-promoting Akt activation in TNBC cells and caused caspase-dependent apoptosis via the mitochondrial pathway, reducing the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, suggesting that piperine can play a role in breast cancer treatment by promoting tumor cell apoptosis and anti-migration.[23]

Matrine

Matrine is the main alkaloid in the traditional Chinese medicine Sophora flavescens, which has been proven to have various pharmacological effects such as anti-inflammatory, antiviral, and immune regulation.[24],[25] Many studies have shown that matrine inhibits the proliferation and metastasis of tumor cells and induces apoptosis. The study found that matrine promoted the apoptosis of human breast cancer MCF-7 cells by up-regulating the ratio of Bax to Bcl-2, thereby exerting a good anti-breast cancer effect.[26] Zhou et al. found that matrine's anti-breast cancer effect is related to regulating the downstream apoptosis factors of PI3K/AKT signal pathway by decreasing cell phosphorylation of AKT level.[27]

Sinomenine

Sinomenine is the main alkaloid extracted from the medicinal plant Sinomenium, which is famous for its anti-inflammatory effects. Recent studies have shown that sinomenine plays an anticancer function in breast cancer and many types of cancer due to its role in cell proliferation inhibition and apoptosis promotion. ERK1/2 plays a role in cell proliferation, and the activation of JNK and p38 MAPKs is usually related to the promotion of apoptosis. Li et al. found that sinomenine induced breast cancer cell death by regulating the expression levels of p-ERK, p-JNK, and p-38 MAPK through reactive oxygen species-dependent and reactive oxygen species-independent pathways.[28] The nuclear factor kappa-light chain enhancer (NF-κB) that activates B-cells is an important transcription factor that regulates a variety of important biological processes, including breast cancer metastasis. Sinomenine treatment inhibits IKK phosphorylation and the activation of NF-κB, which shows an inhibitory effect on breast cancer cell invasion and metastasis.[29] Growing evidence suggests that cancer stem-like side population (SP) is regarded as the “seed” of tumor recurrence and metastasis; the research on the mechanism of invasion and metastasis of SP cells will help to reduce tumor recurrence and metastasis.[30],[31] Studies have found that sinomenine could alleviate the invasion of breast cancer SP cells under hypoxia, possibly through PI3K/Akt/mTOR pathway, which might be a potential drug for breast cancer treatments.[32]

Magnoflorine

Magnoflorine is a quaternary alkaloid isolated from the traditional Chinese medicine Magnolia officinalis or Aristolochia. It has various biological activities such as anti-inflammatory, anticancer, and antianxiety. Doxorubicin (DOX) is a common chemotherapy drug, but its effectiveness is usually limited due to its cardiotoxicity. If a new compound can be found to reduce the concentration of DOX required for anticancer effects, it will definitely benefit breast cancer patients.[33],[34] Studies have found that magnoflorine combined with DOX can promote the sensitivity of MCF-7 and MDA-MB-231 breast cancer cells without cytotoxicity to normal cells. PI3K/AKT/mTOR signaling is a major signaling pathway, which plays a key role in regulating tumor growth. The activation of PI3K/AKT/mTOR can improve cell survival, growth, and protein synthesis, thereby promoting the development of cancer.[35],[36] magnoflorine combined with DOX significantly inhibits breast cancer cell proliferation, migration, and invasion, induces G2/M phase cell distribution and apoptosis through mitochondrial-dependent pathways, and activates autophagy through LC3-II regulated by PI3K/AKT and p38 signaling pathways. Surprisingly, the normal body weight and blood indicators of DOX/magnoflorine-treated mice showed that the combined treatment had almost no side effects in the body, suggesting that magnoflorine can be used as a potential DOX sensitizer.[37]

Cepharanthine

Cepharanthine (CEP) is an alkaloid of Shuanghuanglian extracted from Cephalottis. It has been shown to have antitumor effects on different types of cancer, including inhibiting cell proliferation, inducing autophagic cell death, and preventing metastasis. The mitochondrial pathway is an important mediator of apoptosis, and the Bcl-2 family plays an important role in the mitochondrial pathway.[38] Bcl-2 family members include anti-apoptotic Bcl-2 protein and pro-apoptotic Bax protein. Bax-induced growth arrest is related to the release of cytochrome c from mitochondria, which is blocked by Bcl-2. In the internal apoptotic stimulus, cytochrome c is released into the cytoplasm, where it triggers the formation of apoptotic bodies, thereby activating caspase-9. The caspase-9/apoptotic complex then targets and activates the effector caspase-3.[39] CEP can induce apoptosis by increasing the ratio of Bax/Bcl-2 and activating cleaved caspase-3 and cleaved caspase-9. AKT signaling plays an important role in the regulation of cell proliferation, angiogenesis, migration, and invasion.[40] A large number of studies have shown that mTOR kinase can inhibit autophagy and apoptosis. Gao et al. found that phosphorylated AKT and phosphorylated mTOR in both breast cancer cell lines were reduced after CEP treatment. These data indicate that CEP may induce breast cancer cell apoptosis and autophagy by inhibiting the AKT/mTOR signaling pathway.[41]

Harmine

Harmine (HM) is a β-carboline alkaloid that exhibits significant antitumor activity in vitro and in vivo, including inhibiting proliferation, migration, and invasion, promoting apoptosis, and preventing tumorigenesis. HM inhibits the growth of several cancers, including lung cancer, stomach cancer, breast cancer, and liver cancer.[42],[43] It blocks the cell cycle in the G0/G1 phase, reduces the activity of cyclin-dependent kinases, and increases pro-apoptotic factors, including p53, caspase-3/8/9, Bcl-2, and Bax.[44] Transcriptional coactivator with PDZ-binding motif (TAZ), also known as WW domain-containing transcription regulator 1, serves an important role in the carcinogenesis and progression of breast cancer. TAZ promotes the proliferation, migration, and invasion of breast cancer cells. Chemler et al. found that harmine may induce apoptosis by downregulating TAZ and prevent the proliferation and migration of human breast cancer cells.[45] Invasion and metastasis of breast cancer cells is the main cause of death in breast cancer patients; epithelial-mesenchymal transition is closely related to invasion and metastasis, and Twist1 is a key transcription factor that promotes EMT. Studies have shown that harmine can induce the degradation of Twist1 to test the therapeutic effect of breast cancer.[46]

Tylophorine

Tylophorine is a class of natural alkaloids extracted and isolated from plants such as Rhododendron vulgaris and Gonithium. In the early 1990s, the National Cancer Institute of the United States discovered that many natural products of valerophylline have potential and broad-spectrum antitumor activity. Since then, the antitumor activity of this type of alkaloid has become a research hotspot.[47] Tylophorine plays an important role in the indication of apoptosis of cancer cells through activation of caspase-3 and induces cytochrome c release which then will be bound by Apop-1 (apoptosis-activating factor), which will form apoptosome. Apoptosome will activate caspase-9, and then the caspase-9 will activate caspase-3 that plays a role in apoptosis event. Tylophorine alone or combination with doxorubicin induced apoptosis in T47D breast cancer cells through modulation of cell cycle and upregulating the expression of caspase-3 and caspase-9 enzymes.[48]

Lycorine

Lycorine is an isoquinoline alkaloid that is widely present in Amaryllidaceae plants. It has certain anticancer activity and anti-inflammatory and antipyretic properties. Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that promotes tumor progression and metastasis by affecting the invasion and survival of cancer cells.[49] Lycorine inhibits the growth and metastasis of breast cancer by inducing apoptosis and blocking the Src/FAK pathway.[50] In addition, signal transducer and activator of transcription 3 (STAT3) is the key convergence point of several signal pathways in cancer cells. STAT3 has become a potential anticancer target for various malignant tumors.[51],[52] According to reports, STAT3 is overexpressed and constitutively activated in breast cancer, and its constitutive activation contributes to the progression of breast cancer. Therefore, STAT3 may be a promising target for breast cancer treatment.[53],[54] Studies have shown that lycorine significantly reduces the expression of p-STAT3 and DNA-binding activity in breast cancer cells. Lycorine also reduces the expression of STAT3 regulatory proteins, such as anti-apoptotic proteins (Mcl-1 and Bcl-xL) and invasion-related proteins (MMP-2 and MMP-9).[55]

Sanguinarine

Sanguinarine is extracted from the whole plant with roots of Papaveraceae plant Boluohui and is used to treat many diseases, including cancer. Most complications of breast cancer are attributed to metastasis to distant organs, including lymph nodes, bones, lungs, and liver. Metastasis is considered to be the main cause of death in breast cancer patients. Both MMP-2 and MMP-9 are overexpressed in breast cancer, and are closely related to the metastasis, poor prognosis, and high mortality of breast cancer patients.[56] Therefore, inhibiting the activity and expression of MMP is important for blocking the metastatic ability of breast cancer cells. Cyclooxygenase-2 (COX-2) is overexpressed during breast cancer progression. The upregulation of COX-2 and prostaglandin E2 may participate in the invasion of cancer cells by stimulating the expression of matrix metalloproteinases. Some reports indicate that early inhibition of the activity or expression of MMP-9 and COX-2 enzymes can be used to prevent invasion and cancer metastasis. Experimental evidence proves that heme oxygenase-1 (HO-1) is a key component of multiple signaling pathways that regulate proliferation and metastasis.[57] Increased expression of HO-1 may play an important role in the development and progression of breast cancer. HO-1 expression acts as a negative regulator of premetastatic genes such as MMP-9 and COX-2. Therefore, HO-1 may be an important therapeutic target for the treatment of human breast cancer.[58] Studies have shown that sanguinarine inhibits the activity of MMP-9 and COX-2 in MCF-7 breast cancer cells stimulated by platelet-activating factor by inducing the expression of HO-1, and inhibits the invasion of breast cancer cells.[59] Hypoxia is a key feature leading to tumor progression driven by hypoxia-inducible factor (HIF)-1α. Su et al. found that sanguinarine may potentially be recognized as HIF-1α/STAT3-targeted compound for suppressing breast cancer.[60]

Tetrahydropalmatine

Tetrahydropalmatine is the main active ingredient of Corydalis yanhusuo, a perennial herb of the Papaveraceae family. It has significant analgesic, sedative, antitumor, and other pharmacological effects.[61] It is well known that cells thrive in low levels of reactive oxygen species, but the relative increase in reactive oxygen species can cause cell cycle arrest and apoptosis. Reactive oxygen species modulating drugs have been proposed as a therapeutic strategy to selectively target and destroy cancer cells. Lin et al. found that tetrahydropalmatine has a significant cytotoxic effect on MCF-7 breast cancer cells, reducing the number of cells in a time- and dose-dependent manner. This effect is related to the induction of oxidative stress in cells and the activation of downstream apoptotic pathways.[62]

Oxymatrine

Oxymatrine is the main effective alkaloid component extracted from S. flavescens. It has been proved that oxymatrine can exert antitumor properties in various cancers through different signal pathways. Studies have shown that oxymatrine promotes apoptosis by mediating the expression of Bax and Bcl-2 in the human breast cancer MCF-7 cell line,[63] and studies have found that oxymatrine triggers apoptosis by augmenting cleaved caspase-3 and PARP, inhibits the expression level of anti-apoptotic protein Bcl-2 and the ratio of Bcl-2/Bax in human breast cancer MCF-7 and MDA-MB-231 cells, and induces mitochondrial-mediated apoptosis, which plays a vital role in inhibiting the canceration of breast cancer cells.[64]

Isoliensinine

Isoliensinine is the main dibenzyl isoquinoline alkaloid in lotus embryos. Oxidative stress involves many physiological and pathological processes, including cancer. Reactive oxygen species are the product of normal metabolism and xenobiotic exposure. Excessive reactive oxygen species can induce cell death. Several studies have shown that the apoptotic cell death induced by reactive oxygen species is mediated by p38 MAPK and JNK activation.[65],[66],[67] Cittelly et al. found that isoliensinine can effectively induce apoptosis in triple-negative breast cancer cells; this effect is achieved by inducing oxidative stress and activating p38 and JNK pathways.[68]

Catharanthus alkaloids

Catharanthus alkaloids are alkaloids extracted from the plant Catharanthus roseus. Because of their interference with protein synthesis, their preparations are used clinically as antitumor drugs. Changes in the expression of pro-apoptotic genes and anti-apoptotic genes play a crucial role in the occurrence and development of cancer, and changes in the expression profile of some miRNAs can trigger the regulation of the expression of related apoptosis genes in cells.[69] Hwang et al. confirmed that breast cancer cell apoptosis induced by vinca alkaloids (vincristine, vinblastine, and vinorelbine) is related to the expression of miR-222-3p targeting apoptosis-related genes.[70]

Tomatine

Tomatine can destroy cell membranes and is a strong inhibitor of human cancer cells. In the development of tumor metastasis, the matrix metalloproteinase family plays a very important role in the development of tumors. MMP-2 and MMP-9 work together to cleave the extracellular matrix to increase migration.[71] Tomatine treatment can inhibit matrix metalloproteinase activity and inhibit invasion and metastasis.[72]

Brucine

Brucine is a natural alkaloid. It is reported that brucine possesses anti-invasive and anti-migration, anti-adhesion effects against the highly proliferative and invasive human MDA-MB-231 and Hs578-T breast cancer cell lines by reversing epithelial-mesenchymal transition and downregulating MMP-2 and MMP-9.[73] Surprisingly, brucine was found to treat breast cancer cell bone metastasis; this effect was related to the inhibition of Jagged1/Notch1 signaling pathways.[74]


  Conclusion Top


Judging from the current research results, alkaloid compounds have been widely proven to have pharmacological activities, such as regulating cell cycle, antitumor cell proliferation, and promoting apoptosis, and are candidate drugs for the treatment of breast cancer. However, these studies are limited to animal models and lack clinical validation. We should combine laboratory research with clinical practice to test the reliability of Chinese medicine against breast cancer and promote its application in actual treatment. It is believed that in the near future, efficient alkaloid compounds can be used in specific clinical treatments to maximize the lives of patients and improve the quality of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Eldehna WM, El-Naggar DH, Hamed AR, Ibrahim HS, Ghabbour HA, Abdel-Aziz HA. One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells. J Enzyme Inhib Med Chem 2018;33:309-18.  Back to cited text no. 1
    
2.
Brisken C, Hess K, Jeitziner R. Progesterone and overlooked endocrine pathways in breast cancer pathogenesis. Endocrinology 2015;156:3442-50.  Back to cited text no. 2
    
3.
Varghese E, Samuel SM, Abotaleb M, Cheema S, Mamtani R, Büsselberg D. The “Yin and Yang” of natural compounds in anticancer therapy of triple-negative breast cancers. Cancers (Basel) 2018;10:346.  Back to cited text no. 3
    
4.
Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomised controlled trial. Lancet 2007;369:29-36.  Back to cited text no. 4
    
5.
Gutteridge E, Agrawal A, Nicholson R, Cheung KL, Robertson J, Gee J. The effects of gefitinib in tamoxifen-resistant and hormone-insensitive breast cancer: A phase II study. Int J Cancer 2010;126:1806-16.  Back to cited text no. 5
    
6.
Isakoff SJ. Triple-negative breast cancer: Role of specific chemotherapy agents. Cancer J 2010;16:53-61.  Back to cited text no. 6
    
7.
Li JW, Vederas JC. Drug discovery and natural products: End of an era or an endless frontier? Science 2009;325:161-5.  Back to cited text no. 7
    
8.
Wang K, Tu Y, Wan JB, Chen M, He C. Synergistic anti-breast cancer effect of pulsatilla saponin D and camptothecin through interrupting autophagic-lysosomal function and promoting p62-mediated ubiquitinated protein aggregation. Carcinogenesis 2020;41:804-16.  Back to cited text no. 8
    
9.
El Khalki L, Maire V, Dubois T, Zyad A. Berberine impairs the survival of triple negative breast cancer cells: Cellular and molecular analyses. Molecules 2020;25:506.  Back to cited text no. 9
    
10.
Jabbarzadeh Kaboli P, Rahmat A, Ismail P, Ling KH. Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer. Eur J Pharmacol 2014;740:584-95.  Back to cited text no. 10
    
11.
Sun Y, Wang W, Tong Y. Berberine inhibits proliferative ability of breast cancer cells by reducing metadherin. Med Sci Monit 2019;25:9058-66.  Back to cited text no. 11
    
12.
Zhao Y, Jing Z, Lv J, Zhang Z, Lin J, Cao X, et al. Berberine activates caspase-9/cytochrome c-mediated apoptosis to suppress triple-negative breast cancer cells in vitro and in vivo. Biomed Pharmacother 2017;95:18-24.  Back to cited text no. 12
    
13.
Yao M, Fan X, Yuan B, Takagi N, Liu S, Han X, et al. Berberine inhibits NLRP3 inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell. BMC Complement Altern Med 2019;19:216.  Back to cited text no. 13
    
14.
Hashemi-Niasari F, Rabbani-Chadegani A, Razmi M, Fallah S. Synergy of theophylline reduces necrotic effect of berberine, induces cell cycle arrest and PARP, HMGB1, Bcl-2 family mediated apoptosis in MDA-MB-231 breast cancer cells. Biomed Pharmacother 2018;106:858-67.  Back to cited text no. 14
    
15.
Du J, Sun Y, Lu YY, Lau E, Zhao M, Zhou QM, et al. Berberine and evodiamine act synergistically against human breast cancer MCF-7 cells by inducing cell cycle arrest and apoptosis. Anticancer Res 2017;37:6141-51.  Back to cited text no. 15
    
16.
Gao X, Wang J, Li M, Wang J, Lv J, Zhang L, et al. Berberine attenuates XRCC1-mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs. J Cell Mol Med 2019;23:6797-804.  Back to cited text no. 16
    
17.
Pan Y, Shao D, Zhao Y, Zhang F, Zheng X, Tan Y, et al. Berberine reverses hypoxia-induced chemoresistance in breast cancer through the inhibition of AMPK- HIF-1α. Int J Biol Sci 2017;13:794-803.  Back to cited text no. 17
    
18.
Zhang K, Song H, Yang P, Dai X, Li Y, Wang L, et al. Silencing dishevelled-1 sensitizes paclitaxel-resistant human ovarian cancer cells via AKT/GSK-3β/β-catenin signalling. Cell Prolif 2015;48:249-58.  Back to cited text no. 18
    
19.
Gupta N, Gupta P, Srivastava SK. Penfluridol overcomes paclitaxel resistance in metastatic breast cancer. Sci Rep 2019;9:5066.  Back to cited text no. 19
    
20.
Das Mukherjee D, Kumar NM, Tantak MP, Datta S, Ghosh Dastidar D, Kumar D, et al. NMK-BH2, a novel microtubule-depolymerising bis (indolyl)-hydrazide-hydrazone, induces apoptotic and autophagic cell death in cervical cancer cells by binding to tubulin at colchicine – Site. Biochim Biophys Acta Mol Cell Res 2020;1867:118762.  Back to cited text no. 20
    
21.
Gallego-Jara J, Lozano-Terol G, Sola-Martínez RA, Cánovas-Díaz M, de Diego Puente T. A compressive review about Taxol®: History and future challenges. Molecules 2020;25:5986.  Back to cited text no. 21
    
22.
Do MT, Kim HG, Choi JH, Khanal T, Park BH, Tran TP, et al. Antitumor efficacy of piperine in the treatment of human HER2-overexpressing breast cancer cells. Food Chem 2013;141:2591-9.  Back to cited text no. 22
    
23.
Greenshields AL, Doucette CD, Sutton KM, Madera L, Annan H, Yaffe PB, et al. Piperine inhibits the growth and motility of triple-negative breast cancer cells. Cancer Lett 2015;357:129-40.  Back to cited text no. 23
    
24.
Zhou J, Ma W, Wang X, Liu H, Miao Y, Wang J, et al. Matrine suppresses reactive oxygen species (ROS)-mediated MKKs/p38-induced inflammation in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages. Med Sci Monit 2019;25:4130-6.  Back to cited text no. 24
    
25.
Wang JK, Zhao BS, Wang M, Liu CY, Li YQ, Ma QT, et al. Anti-tumor and phenotypic regulation effect of matrine on dendritic cells through regulating TLRs pathway. Chin J Integr Med 2021;27:520-6.  Back to cited text no. 25
    
26.
Li H, Li X, Bai M, Suo Y, Zhang G, Cao X. Matrine inhibited proliferation and increased apoptosis in human breast cancer MCF-7 cells via upregulation of Bax and downregulation of Bcl-2. Int J Clin Exp Pathol 2015;8:14793-9.  Back to cited text no. 26
    
27.
Zhou BG, Wei CS, Zhang S, Zhang Z, Gao HM. Matrine reversed multidrug resistance of breast cancer MCF-7/ADR cells through PI3K/AKT signaling pathway. J Cell Biochem 2018;119:3885-91.  Back to cited text no. 27
    
28.
Li X, Wang K, Ren Y, Zhang L, Tang XJ, Zhang HM, et al. MAPK signaling mediates sinomenine hydrochloride-induced human breast cancer cell death via both reactive oxygen species-dependent and -independent pathways: An in vitro and in vivo study. Cell Death Dis 2014;5:e1356.  Back to cited text no. 28
    
29.
Song L, Liu D, Zhao Y, He J, Kang H, Dai Z, et al. Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis. Biochem Biophys Res Commun 2015;464:705-10.  Back to cited text no. 29
    
30.
Gao G, Sun Z, Liu W, Ye D, Zhao R, Zhang X. A preliminary study of side population cells in human gastric cancer cell line HGC-27. Ann Transplant 2015;20:147-53.  Back to cited text no. 30
    
31.
Niess H, Camaj P, Renner A, Ischenko I, Zhao Y, Krebs S, et al. Side population cells of pancreatic cancer show characteristics of cancer stem cells responsible for resistance and metastasis. Target Oncol 2015;10:215-27.  Back to cited text no. 31
    
32.
Song L, Zhang H, Hu M, Liu C, Zhao Y, Zhang S, et al. Sinomenine inhibits hypoxia induced breast cancer side population cells metastasis by PI3K/Akt/mTOR pathway. Bioorg Med Chem 2021;31:115986.  Back to cited text no. 32
    
33.
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: Pharmacodynamics and adverse effects. Pharmacogenet Genomics 2011;21:440-6.  Back to cited text no. 33
    
34.
Seebacher NA, Richardson DR, Jansson PJ. A mechanism for overcoming P-glycoprotein-mediated drug resistance: Novel combination therapy that releases stored doxorubicin from lysosomes via lysosomal permeabilization using Dp44mT or DpC. Cell Death Dis 2016;7:e2510.  Back to cited text no. 34
    
35.
Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev 2014;40:862-71.  Back to cited text no. 35
    
36.
Nunnery SE, Mayer IA. Targeting the PI3K/AKT/mTOR pathway in hormone-positive breast cancer. Drugs 2020;80:1685-97.  Back to cited text no. 36
    
37.
Wei T, Xiaojun X, Peilong C. Magnoflorine improves sensitivity to doxorubicin (DOX) of breast cancer cells via inducing apoptosis and autophagy through AKT/mTOR and p38 signaling pathways. Biomed Pharmacother 2020;121:109139.  Back to cited text no. 37
    
38.
Adams JM, Cory S. The Bcl-2 protein family: Arbiters of cell survival. Science 1998;281:1322-6.  Back to cited text no. 38
    
39.
Manon S, Chaudhuri B, Guérin M. Release of cytochrome c and decrease of cytochrome c oxidase in Bax-expressing yeast cells, and prevention of these effects by coexpression of Bcl-xL. FEBS Lett 1997;415:29-32.  Back to cited text no. 39
    
40.
Manning BD, Cantley LC. AKT/PKB signaling: Navigating downstream. Cell 2007;129:1261-74.  Back to cited text no. 40
    
41.
Gao S, Li X, Ding X, Qi W, Yang Q. Cepharanthine induces autophagy, apoptosis and cell cycle arrest in breast cancer cells. Cell Physiol Biochem 2017;41:1633-48.  Back to cited text no. 41
    
42.
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.  Back to cited text no. 42
    
43.
Zhang L, Zhang F, Zhang W, Chen L, Gao N, Men Y, et al. Harmine suppresses homologous recombination repair and inhibits proliferation of hepatoma cells. Cancer Biol Ther 2015;16:1585-92.  Back to cited text no. 43
    
44.
Ding Y, He J, Huang J, Yu T, Shi X, Zhang T, et al. Harmine induces anticancer activity in breast cancer cells via targeting TAZ. Int J Oncol 2019;54:1995-2004.  Back to cited text no. 44
    
45.
Chemler SR. Phenanthroindolizidines and phenanthroquinolizidines: Promising alkaloids for anti-cancer therapy. Curr Bioact Compd 2009;5:2-19.  Back to cited text no. 45
    
46.
Nafie E, Lolarga J, Lam B, Guo J, Abdollahzadeh E, Rodriguez S, et al. Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1. PLoS One 2021;16:e0247652.  Back to cited text no. 46
    
47.
Pratama NP, Wulandari S, Nugroho AE, Fakhrudin N, Astuti P, Sudarsono. Tylophorine abrogates G2/M arrest induced by doxorubicine and promotes increased apoptosis in T47D breast cancer cells. Asian Pac J Cancer Prev 2018;19:3065-9.  Back to cited text no. 47
    
48.
Shibue T, Brooks MW, Inan MF, Reinhardt F, Weinberg RA. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov 2012;2:706-21.  Back to cited text no. 48
    
49.
Ying X, Huang A, Xing Y, Lan L, Yi Z, He P. Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway. Sci China Life Sci 2017;60:417-28.  Back to cited text no. 49
    
50.
Zhao M, Jiang B, Gao FH. Small molecule inhibitors of STAT3 for cancer therapy. Curr Med Chem 2011;18:4012-8.  Back to cited text no. 50
    
51.
Aydiner A. Meta-analysis of breast cancer outcome and toxicity in adjuvant trials of aromatase inhibitors in postmenopausal women. Breast 2013;22:121-9.  Back to cited text no. 51
    
52.
Diaz N, Minton S, Cox C, Bowman T, Gritsko T, Garcia R, et al. Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res 2006;12:20-8.  Back to cited text no. 52
    
53.
Germain D, Frank DA. Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 2007;13:5665-9.  Back to cited text no. 53
    
54.
Wang J, Xu J, Xing G. Lycorine inhibits the growth and metastasis of breast cancer through the blockage of STAT3 signaling pathway. Acta Biochim Biophys Sin (Shanghai) 2017;49:771-9.  Back to cited text no. 54
    
55.
Jinga DC, Blidaru A, Condrea I, Ardeleanu C, Dragomir C, Szegli G, et al. MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: Correlations with prognostic factors. J Cell Mol Med 2006;10:499-510.  Back to cited text no. 55
    
56.
Farombi EO, Surh YJ. Heme oxygenase-1 as a potential therapeutic target for hepatoprotection. J Biochem Mol Biol 2006;39:479-91.  Back to cited text no. 56
    
57.
Jozkowicz A, Was H, Dulak J. Heme oxygenase-1 in tumors: Is it a false friend? Antioxid Redox Signal 2007;9:2099-117.  Back to cited text no. 57
    
58.
Park SY, Jin ML, Kim YH, Lee SJ, Park G. Sanguinarine inhibits invasiveness and the MMP-9 and COX-2 expression in TPA-induced breast cancer cells by inducing HO-1 expression. Oncol Rep 2014;31:497-504.  Back to cited text no. 58
    
59.
Zhang MY, Liu YP, Zhang LY, Yue DM, Qi DY, Liu GJ, et al. Levo-tetrahydropalmatine attenuates bone cancer pain by inhibiting microglial cells activation. Mediators Inflamm 2015;2015:752512.  Back to cited text no. 59
    
60.
Su Q, Wang J, Fan M, Ghauri MA, Ullah A, Wang B, et al. Sanguinarine disrupts the colocalization and interaction of HIF-1α with tyrosine and serine phosphorylated-STAT3 in breast cancer. J Cell Mol Med 2020;24:3756-61.  Back to cited text no. 60
    
61.
Sivakumaran N, Samarakoon SR, Adhikari A, Ediriweera MK, Tennekoon KH, Malavige N, et al. Cytotoxic and apoptotic effects of govaniadine isolated from Corydalis govaniana Wall. roots on human breast cancer (MCF-7) cells. Biomed Res Int 2018;2018:3171348.  Back to cited text no. 61
    
62.
Lin B, Li D, Zhang L. Oxymatrine mediates Bax and Bcl-2 expression in human breast cancer MCF-7 cells. Pharmazie 2016;71:154-7.  Back to cited text no. 62
    
63.
Wu J, Cai Y, Li M, Zhang Y, Li H, Tan Z. Oxymatrine promotes S-phase arrest and inhibits cell proliferation of human breast cancer cells in vitro through mitochondria-mediated apoptosis. Biol Pharm Bull 2017;40:1232-9.  Back to cited text no. 63
    
64.
Kim JY, Yu SJ, Oh HJ, Lee JY, Kim Y, Sohn J. Panaxydol induces apoptosis through an increased intracellular calcium level, activation of JNK and p38 MAPK and NADPH oxidase-dependent generation of reactive oxygen species. Apoptosis 2011;16:347-58.  Back to cited text no. 64
    
65.
Ramiro-Cortés Y, Guemez-Gamboa A, Morán J. Reactive oxygen species participate in the p38-mediated apoptosis induced by potassium deprivation and staurosporine in cerebellar granule neurons. Int J Biochem Cell Biol 2011;43:1373-82.  Back to cited text no. 65
    
66.
Hsieh CJ, Kuo PL, Hsu YC, Huang YF, Tsai EM, Hsu YL. Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation. Free Radic Biol Med 2014;67:159-70.  Back to cited text no. 66
    
67.
Zhang X, Wang X, Wu T, Li B, Liu T, Wang R, et al. Isoliensinine induces apoptosis in triple-negative human breast cancer cells through ROS generation and p38 MAPK/JNK activation. Sci Rep 2015;5:12579.  Back to cited text no. 67
    
68.
Cittelly DM, Das PM, Salvo VA, Fonseca JP, Burow ME, Jones FE. Oncogenic HER2{Delta} 16 suppresses miR-15a/16 and deregulates BCL-2 to promote endocrine resistance of breast tumors. Carcinogenesis 2010;31:2049-57.  Back to cited text no. 68
    
69.
Mavrogiannis AV, Kokkinopoulou I, Kontos CK, Sideris DC. Effect of vinca alkaloids on the expression levels of microRNAs targeting apoptosis-related genes in breast cancer cell lines. Curr Pharm Biotechnol 2018;19:1076-86.  Back to cited text no. 69
    
70.
Hwang BM, Chae HS, Jeong YJ, Lee YR, Noh EM, Youn HZ, et al. Protein tyrosine phosphatase controls breast cancer invasion through the expression of matrix metalloproteinase-9. BMB Rep 2013;46:533-8.  Back to cited text no. 70
    
71.
Gong Y, Chippada-Venkata UD, Oh WK. Roles of matrix metalloproteinases and their natural inhibitors in prostate cancer progression. Cancers (Basel) 2014;6:1298-327.  Back to cited text no. 71
    
72.
Yelken BÖ, Balcı T, Süslüer SY, Kayabaşı Ç, Avcı ÇB, Kırmızıbayrak PB, et al. The effect of tomatine on metastasis related matrix metalloproteinase (MMP) activities in breast cancer cell model. Gene 2017;627:408-11.  Back to cited text no. 72
    
73.
Li M, Li P, Zhang M, Ma F. Brucine suppresses breast cancer metastasis via inhibiting epithelial mesenchymal transition and matrix metalloproteinases expressions. Chin J Integr Med 2018;24:40-6.  Back to cited text no. 73
    
74.
Hu KF, Kong XY, Zhong MC, Wan HY, Lin N, Pei XH. Brucine inhibits bone metastasis of breast cancer cells by suppressing Jagged1/Notch1 signaling pathways. Chin J Integr Med 2017;23:110-6.  Back to cited text no. 74
    



 
 
    Tables

  [Table 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Definition of Al...
The Effect and M...
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed1435    
    Printed22    
    Emailed0    
    PDF Downloaded191    
    Comments [Add]    

Recommend this journal