The anti-tumor potential of sinomenine: a narrative review

Introduction

Since the second half of the 20th century, the incidence and mortality rates of cancer have been increasing year by year. According to statistics, in 2019, cancer became the fourth leading cause of death among young people worldwide (1). In 2023, there will be about 1,958,310 new cases of cancer worldwide and about 609,820 deaths occur in the United States (2). In recent years, Chinese herbal medicine has been playing an important role in the treatment of malignant tumors. Sinomenine has attracted the attention of scholars again because of its anti-tumor activity. Sinomenium acutum was used to treat rheumatic diseases more than 1,000 years ago. In the early 20th century, Japanese scholars isolated its main active ingredient from plant ivy (3). Its molecular formula is C₁₉H₂₃NO₄. Since sinomenine was discovered, scholars across the world have confirmed the cytotoxic effect of sinomenine on a variety of cancer cells in vitro and in vivo. It has been found to have many functions, such as anti-inflammatory, analgesic, immunomodulation, anti-tumor and drug addiction effects (4). Researchers have suggested that sinomenine is an effective chemoprophylaxis agent for cancer. However, sinomenine has the disadvantages of unstable physicochemical properties, poor water solubility, short half-life and low bioavailability, which limits its activity against cancer. Therefore, nanocarriers and molecular modification (such as sinomenine hydrochloride, sinomenine ester derivatives, chlorine-containing derivatives and YL064) is considered an effective method to solve these problems (5). Sinomenine has been successfully loaded into transmitter to enhance its bioactivity and bioavailability (6). Compared with sinomenine, Exo-SIN, a mixture of sinomenine and exosomes constructed by Wang et al., showed significantly stronger cytotoxicity in HepG2 cells and significantly inhibited cell cycle arrest and apoptosis of hepatoma cells (7). Moreover, sinomenine also reduces osteolysis and bone pain in cancer patients. This review summarizes the molecular mechanism and potential value of sinomenine in the treatment of malignant tumors from the above aspects to provide a reference for the clinical transformation of sinomenine. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-267/rc).

Methods

A literature search was conducted in Medline and PubMed databases using the keywords “Sinomenine” AND “Tumor” OR “Pharmacological mechanism”. The secondary references cited in articles obtained from the Medline and PubMed search were also retrieved. Methodology of the search is summarized in the Table 1.

In this study, 34 studies on the anti-tumor mechanism of sinomenine were included by searching the databases of PubMed and Web of Science. It was concluded that sinomenine and its derivatives played an anti-tumor role mainly by promoting apoptosis and autophagy, inhibiting proliferation, migration and invasion, and enhancing sensitivity to chemoradiotherapy (Table 2).

Sinomenine inhibits tumor cell proliferation

PI3K/AKT signalling pathway

Mutations and aberrant activation of the PI3K/AKT signalling pathway affect the proliferation, autophagy, migration, invasion and metabolism of cancer cells (41). Recently, AKT has been widely studied as a therapeutic target in cancer, and the AKT inhibitor capivasertib has been recognized as an effective targeting drug for tumors and has been approved for clinical use. Duan et al. reported that the proliferative capacity of HeLa cells decreased with increasing sinomenine concentration (8). In addition, researchers found that sinomenine inhibited the activation of p-PI3K and p-AKT and the expression of Ki67 and PCNA in a dose-dependent manner in breast cancer, renal cell carcinoma and cholangiocarcinoma. Moreover, activation of the PI3K/AKT pathway attenuated the inhibition of tumor cell proliferation (16,25). For example, Chen et al. showed that sinomenine hydrochloride inhibited the proliferation of mantle cell lymphoma by inhibiting the phosphorylation level of the AKT/mTOR/P70S6K pathway (36). In addition, Liu et al. demonstrated that hexokinase II (HK2) was highly expressed in non-small cell lung cancer tissues and cell lines, while sinomenine reduced the expression levels of HK2, p-AKT and its downstream kinase S6 (18). Moreover, after AKT knockdown, the expression level of HK2, glycolysis and proliferation ability of cells were inhibited, while overexpression of AKT reversed the above changes. This study showed that sinomenine could inhibit ovarian cancer cell proliferation by reducing the activity of p-AKT and its downstream kinase S6, thereby downregulating glycolysis mediated by HK2. Deng et al. also demonstrated that sinomenine inhibits renal cancer cell proliferation by promoting the inhibition of PI3K/AKT/mTOR signalling pathway by reactive oxygen species (25). In conclusion, sinomenine and its derivatives can inhibit tumor proliferation by regulating AKT-related signalling pathways.

Stemness of tumor cells

Cancer stem cells with the abilities of self-renewal, proliferation and differentiation play an important role in the survival, proliferation, metastasis and recurrence of tumors. Because cancer stem cells can be dormant for a long time, they are not sensitive to radiotherapy and chemotherapy, which seriously affects the anti-tumor effect. Thus, targeted cancer stem cell therapy may be an emerging strategy for anti-tumor development. CD44/CD24 is currently a well-recognized stem cell marker in breast cancer. Li et al. team showed that in breast cancer, sinomenine hydrochloride could inhibit the activity of Wnt/β-catenin signalling pathway by downregulating the expression of WNT10B, thus inhibiting the percentage of CD44/CD24 in MDA-MB-231 and MCF-7 cell lines and inhibiting the expression of breast cancer stem cell-related genes (including JUN, MET, MYC, INHBB, CHCR4, HMGA2 and TGFB2) (9). This study demonstrated that sinomenine hydrochloride can inhibit the stemness of breast cancer stem cells in vivo and in vitro by negatively regulating WNT10B expression. In conclusion, sinomenine and its derivatives can inhibit tumor proliferation by inhibiting the stemness of cancer cells.

Cell cycle

Cell cycle regulation contains three checkpoints, namely G1/S, G2/M and the mitotic spindle checkpoint. Dysregulation of the cell cycle causes normal cells to enter a state of uncontrolled growth and transform into tumor cells. Meanwhile, the tumor cells also depend on the cell cycle for their proliferation. Cyclins and cyclin-dependent kinases (CDK) are important positive regulators of the cell cycle. A variety of compounds targeting CDK have recently been developed to inhibit the activity of CDK by blocking the cell cycle to inhibit tumor cell proliferation. Qu et al. suggested that the expression of cell cycle regulators such as CDK 1, PLK 1, and BUB 1 and the phosphorylation of histone H3 were significantly reduced in ovarian cancer after the sinomenine treatment (15). Moreover, the G2/M transition in ovarian cancer cells was inhibited, thereby inhibiting mitosis. Among them, histone H3 is closely associated with chromosome condensation during mitosis. In addition, Xu et al. have shown that sinomenine hydrochloride inhibited ovarian cancer cell growth by reducing the expression of long non-coding RNA-HOST 2, thus downregulating Cyclin D1, CDK 4 and CDK 6 to induce cell G0/G1 phase arrest (19). In myeloma, YL064, a derivative of sinomenine, inhibited of myeloma cell proliferation by inhibiting the nuclear translocation of STAT3 and the expression of its target gene Cyclin D1 (39). In conclusion, sinomenine and its derivatives can significantly inhibit the proliferation of a variety of tumor cells by blocking the cell cycle.

Non-coding RNA

Non-coding RNAs is involved in all stages of tumor initiation, development and metastasis, and they are constantly being discovered as disease markers and targets for tumor treatment. Among them, miRNA can promote the deadenylation and degradation of the target mRNA to regulate the protein expression level. In addition, lncRNAs act as ceRNAs to absorb miRNAs to regulate the expression of related genes. It can also cooperate with transcription factors to activate related genes, or directly bind to the protein to prevent its degradation, promoting protein function. Among them, miR-29 has the dual role of tumor suppressor and procancer and has been recognized to play a key role in cancer pathogenesis. More than 85% of miR-29-related studies have shown that it suppresses multiple cancer-related targets to exert anti-tumor effects (42). Gao et al. showed that sinomenine hydrochloride could block the JNK and MEK/ERK pathways by upregulating miR-29/PDCD4 expression to inhibit the proliferation of breast cancer cells (20). LncRNA-HEIH is carcinogenic in various cancers. Xu et al. found that lncRNA-HEIH was upregulated in bladder cancer cell lines (T24,5637, HT-1197, TCCSUP and SW 780) (12). However, sinomenine can downregulate the expression of lncRNA-HEIH, and knockdown of lncRNA-HEIH reversed the inhibition of proliferation in bladder cancer cells. Overall, sinomenine and its derivatives can inhibit tumor cell proliferation by regulating the expression of non-coding RNAs and theirs target genes.

Sinomenine induces tumor cell apoptosis

p21 leads to CDK2/cyclin-E activation and ribosome phosphorylation

As an effective inhibitor of CDK, p21 can not only block the cell cycle and inhibit cell proliferation, but also promote cell apoptosis. p53 can not only induce the expression of p21 but also form a complex with p21 to play an anti-tumor role. For example, p53 and p21 can form a complex with Bcl-2 family proteins to release Bax proteins and promote the apoptosis of tumor cells (43). In glioblastoma, SW33, a sinomenine derivative, causes G2/M arrest and cell apoptosis by regulating p53/p21 signaling pathway and the activity of the CCNB1/CDC2 complex, inducing cell apoptosis (11). As a key regulator of the cell cycle and cell apoptosis, Survivin is only expressed in tumor and embryonic tissues. Survivin could inhibit the activity of Caspasc-3 and Caspasc-7 either directly or indirectly through p21. Survivin can also bind to the cell cycle regulator CDK 4 to accelerate the G1/S phase conversion and release p21, causing it to bind and inhibit caspase-3 activity, thus preventing mitochondria from releasing cytochrome C to inhibit apoptosis (44). In Lu et al.’s study, sinomenine hydrochloride downregulated Survivin to upregulated p21 expression levels and promoted the release of cytochrome c and Omi/HtrA 2 from mitochondria into the cytosol, promoting mitochondrial apoptosis in hepatocellular carcinoma cells (33).

MAPK signalling pathway

As a tumor suppressor, MAPK has four main subfamilies: ERK 1/2, p38 MAPK, JNK, and ERK 5. Among them, the JNK and p38 signalling pathways regulate cell apoptosis by targeting various genes (including Bcl-2, Bax and cyclin D1). Sinomenine can have chemopreventive properties by altering the level of oxidative stress in tumors. In Gao et al.’s study, sinomenine upregulates PDCD4 expression by mediating miR-29; PDCD4 obstructs the JNK and MEK/ERK pathways in MDA-MB-231 cells (20). However, the ERK signalling pathway is a double-edged sword in tumors. On the one hand, its inhibitors BPI-27336, HH2710, and HMPL-295S1 have been used clinically as anti-tumor drugs. On the other hand, the ERK 1/2 kinase has similar proapoptotic functions, namely, the activation of the ERK signalling pathway can also lead to the apoptosis of tumor cells. In addition, α7 nicotinic acetylcholine receptor (α7 nAChR) was first identified as a neuromodulator, and its overexpression was later proven to be closely related to the proliferation, and apoptosis, specifically, invasion of cancer cells (45). α7 nAChR and its major upstream regulator ERK 1/2 are also involved in the anti-tumor mechanism of sinomenine. In lung cancer, sinomenine can promote apoptosis in lung cancer cells by inhibiting ERK 1/2 phosphorylation and mediating α7 nAChR levels. Moreover, sinomenine not only downregulated the positive regulators of α7 nAChR—SP 1 and TTF-1—but also upregulated its negative regulator—Egr-1 (14).

AKT signalling pathway

In addition to proliferation, several studies have demonstrated that AKT signalling is involved in the mechanism by which picoline promotes tumor cell apoptosis. Liu et al. showed that sinomenine can regulate Bcl-2, Bax and caspase-3 by downregulating of p-AKT in non-small cell lung cancer (18). Among them, overexpression of HK2 reduced the induction of mitochondrial apoptosis in non-small cell lung cancer cells. Moreover, HK2 expression was also decreased with AKT knockdown. That is, sinomenine can promote apoptosis in non-small cell lung cancer by inhibiting HK2 activation by p-AKT. Similarly, Deng et al. showed that sinomenine induced apoptosis in renal cancer cells through activation of the mitochondrial apoptotic pathway, while activation of the PI3K/AKT signalling pathway antagonized sinomenine-induced apoptosis in renal cancer cells (25). Similarly, Chen et al. showed that sinomenine hydrochloride could regulate the expression of Cyclin D1, BCL-2, BAX and caspase-3 through downregulation of p-AKT levels, thereby promoting apoptosis in mantle cell lymphoma cells (36).

The others

Similar to the mechanism by which sinomenine inhibits cell proliferation, sinomenine and its derivatives can also activate the mitochondrial apoptosis pathway in bladder cancer and hepatocellular carcinoma by downregulating lncRNA-HEIH and miR-29 (12,20). In addition, sinomenine can induce apoptosis of pancreatic cancer cells by inducing G0/G1 cell cycle arrest and apoptosis of malignant glioma and liver cancer cells (35). Among them, the AMPK/STAT3 signalling pathway mediated by the MARCH1 gene is also involved in the mechanism by which sinomenine promotes apoptosis in hepatoma cells (28).

Sinomenine induces tumor cell migration and invasion

miRNA

miRNAs are widely involved in the regulation of gene expression during tumor migration and invasion. In the development of tumors, miR-21 acts as a proto-oncogene, which negatively regulates the tumor suppressor genes TPM1, PDCD4 and MASPIN. Several studies have shown that miR-324-5p has antitumor effects in some tumors, and the aberrant reduction in its expression is related to the proliferation, differentiation, metastasis and invasion of tumor cells (46,47). However, in another subset of tumors, miR-324-5p promoted tumor cell viability and invasion and migration (48). Zhang et al. showed that the expression of miR-324-5p was significantly downregulated in gallbladder cancer tissues and cells compared with normal gallbladder tissue, and the level of miR-324-5p was negatively correlated with the degree of tumor invasion and metastasis (47). Several studies have shown that sinomenine and its derivatives can upregulate E-cadherin, TIMP-1/2, downregulate the expression levels of MMP2, MMP9, N-cadherin, vimentin, and EphA2, and inhibit the progression of epithelial epithelial-mesenchymal transition (EMT) and the migration and invasion of cancer cells (17,27). Song et al. showed that sinomenine could inhibit the SIAH2/HIF-1α axis by upregulating miR-324-5p, and that inhibition of miR-324-5p or overexpression of SIAH 2 counteracted the inhibition of EMT in breast cancer cells (10). Moreover, sinomenine downregulated miR-21, which promoted the expression of RECK, TIMP-1/-2 and E-cadherin, and decreased the expression of MMP2/MMP9 and Vimentin (17). In addition to inhibiting proliferation, sinomenine hydrochloride can also inhibit the migration and invasion of breast cancer cells by inhibiting the miR-29/PDCD4 axis (20).

TGF-β/Smad signalling pathway

EMT induced by TGF-β signalling is necessary for tumor metastasis, and its components are dysregulated in multiple tumors. Among them, in the classical TGF-β signalling pathway, receptor activation induces phosphorylation at the SMAD C-terminus, and phosphorylated SMADs form a complex with SMAD4 and promote SMAD4 translocation to bind to target gene promoters in the nucleus, controlling the transcription of hundreds of genes. Among them, SMAD1/7 plays a critical role in EMT progression induced by TGF-β. In the nonclassical TGF-β signalling pathway, TGF-β receptors are activated through other signalling pathways, such as the MAPK (ERK, p38 and JNK), AKT and Rho GTPase pathways, which are indirectly involved in cell EMT, proliferation, apoptosis and other cellular activities. Zhao et al. showed that sinomenine hydrochloride not only inhibited the TGF-β/Smad signaling pathway, and depleted p-Smad 2 and p-Smad 3, but also inhibited the EMT-related transcription factors Snail1 and Twist to inhibit EMT (26). Studies have also shown that sinomenine and its derivatives can inhibit the migration and invasion of cancer cells by inhibiting PI3K/Akt/mTOR activation and MAPK (ERK, p38 and JNK) signalling pathways (14,16,49).

STAT3 and NF-κB signaling pathway

Chronic inflammation is a trigger for tumor proliferation and migration, while STAT3 and NF-κB are the focus of inflammation and cancer research. The two interact at multiple levels to activate the transcription of their common downstream target genes and promote tumor development and progression. Wang et al. showed that the sinomenine derivative YL064, a novel STAT3 inhibitor with promising anti-myeloma activity, may prevent the interaction of STAT3 with phosphorylated tyrosine residues on cytoplasmic receptor kinases by targeting the SH2 domain of STAT3 (29). Song et al. showed that sinomenine could inhibit the migration and invasion capacity of breast cancer cells by inhibiting NF-κB activation and NF-κB-mediated activation of the SHh signalling pathway (23,50).

Sinomenine induces tumor cell autophagy

Autophagy is an intracellular degradation mechanism that is a double-edged sword for tumors. On the one hand, autophagy can provide energy for cancer cells in nutrient deficient conditions for a long time and improve their tolerance in stress environments such as starvation, hypoxia, and chemoradiotherapy. On the other hand, autophagy can protect normal cells and maintain homeostasis against malignant changes, and excessive autophagy can also induce autophagic death in tumors. The mechanism of autophagy regulation in cancer involves signalling pathways such as the PI3K/AKT/mTOR, MAPK/mTOR, and AMPK/mTOR pathways and autophagy-related proteins (LC3B, ATG, Beclin-1, and P62) (51). The study suggested that treatment with the sinomenine ester derivative SW33 and sinomenine hydrochloride increased the number of phagosomes and phagolysosomes in U87 and U251 and SF767 cells, the transition of LC3BI to membrane-bound LC3BII, and increased the levels of ATG5 and Becline1. Moreover, the PI3K/AKT/mTOR, AMPK/mTOR and JNK signalling pathways are all involved in the mechanism by which sinomenine and its derivatives promote autophagy in glioblastoma cells (11).

Sinomenine enhances sensitivity to chemotherapy or radiotherapy, reverses drug resistance, and alleviates tumor complications

Although radiotherapy and chemotherapy have become two powerful tools in the treatment of many cancers, after a long period of treatment, the tumor may be tolerant to chemotherapy and radiotherapy, and the adverse reactions of radiotherapy and chemotherapy negatively affect the cooperation of patients. This situation is undoubtedly a huge challenge for clinicians. Therefore, the enhancement of chemoradiotherapy sensitivity and the reversal of drug resistance have become a research focus in recent years.

Sinomenin enhances chemosensitivity

5-Fluorouracil (5-FU) has a wide anti-cancer spectrum, and mainly serves as the preferred chemotherapeutic agent for digestive system tumors. Cisplatin, as a first-line anticancer drug, is mostly used in the treatment of various solid tumors, such as ovarian cancer, prostate cancer, testicular cancer, lung cancer, thyroid cancer and osteosarcoma. However, its severe side effects and drug resistance hinder its clinical application. At present, it has been found that sinomenine and its derivatives can not only enhance the sensitivity of liver cancer (13), colon cancer (31), gastric cancer (32), and oesophageal cancer (38) to 5-FU, but also enhance the sensitivity of gastric cancer (52) to cisplatin and the sensitivity of breast cancer to tamoxifen. First, sinomenine could enhance the sensitivity of MCF-7 cells to TAM in breast cancer by inhibiting the hyperactivation of the PI3K/AKT/mTOR signalling pathway, and then reverse the resistance of MCF-7 cells to tamoxifen. Second, sinomenine can further enhance the sensitivity of tumor cells to 5-FU and cisplatin through the induction of apoptosis and growth inhibition (32,52). For example, sinomenine can sensitize human gastric cancer cells to cisplatin through downregulation of the PI3K/AKT/Wnt signalling pathway. Moreover, Duan et al.’s study showed that sinomenine suppresses the Trx/TrxR system, and the high expression of TrxR is closely related to chemoresistance (8). Moreover, it is noteworthy that sinomenine does not increase chemotherapeutic side effects when enhancing tumor cell sensitivity to 5-FU (31).

Sinomenine enhances radiotherapy sensitivity

Radiotherapy occurs through the use of ionizing radiation with high-energy rays, changing the cell structure and directly or indirectly acting on the DNA, causing the breakage and cross-linking of DNA molecules, resulting in cell death. During radiotherapy, some cells continued to survive after DNA repair, and anaerobic cells and cells in early G1 have poor sensitivity to radiation, while oxygen-rich cells and cells in G2/M phase are the most sensitive to radiation. Zhang et al. have demonstrated in a mouse xenograft model of cervical cancer that sinomenine hydrochloride prevents DNA repair by inhibiting the expression of the DNA damage response factors Ku80 and Rad 51 to enhance the sensitivity of cervical cancer to radiotherapy (22). In oesophageal cancer, sinomenine hydrochloride can increase radiation sensitivity in ESCC cells by inducing G2/M phase arrest, promoting radiation-induced apoptosis and inhibiting the DNA double strand break (DSB) repair pathway (34). Zhao et al. suggests that sinomenine hydrochloride may be a potential sensitizer for papillary thyroid cancer after total thyroidectomy, which is related to the downregulation of Bcl-2 and Bax protein expression and the upregulation of Fas, p21, p-ATM, p-Chk 1, p-Chk 2, and p53 protein expression (40).

Sinomenine relieves tumor complications

Bone metastases often occur in various cancers to advanced stages, such as lung cancer, breast cancer, and prostate cancer. Bone metastasis can lead to a variety of bone complications, such as osteolysis, fracture, hypercalcaemia and bone pain, which can seriously reduce the quality of life of patients and increase patient mortality. Among them, bone pain is one of the most common and severe types of cancer pain. Currently, radiotherapy is the treatment of choice for patients with such tumors, but many patients need a combination of analgesic drugs to provide effective pain relief. Among them, the osteoclasts treatment is considered the most effective strategy to alleviate bone destruction caused by cancer cell bone metastasis and reduce bone-related events (such as pain and fractures) and thus improving the quality of life of patients (53). Sinomenine is widely used in the treatment of rheumatoid arthritis because of its anti-inflammatory and analgesic effects and few side effects. In addition, sinomenine can be used to treat osteolysis caused by rheumatoid arthritis. It has been demonstrated that sinomenine suppresses osteoclast genesis and osteolysis induced by human nuclear factor-activated factor receptor ligand and lipopolysaccharide (54). Subsequently, it was been demonstrated that sinomenine could inhibit osteoclast formation and osteolytic injury in breast cancer cells by reducing IL-8 and c-Fos/NFATc1 (21).

Conclusions

This review has the following improvement from the review by Gao et al. published in 2019 (55). First, nanocarriers and molecular modifications are considered to be effective methods for the development and utilization of sinomenine. Therefore, in addition to sinomenine, our review also described the anti-tumor effects of derivatives of sinomenine. And suggested that it is still necessary to improve the water solubility and bioavailability of sinomenine by using new technologies and new processes, such as drug synthesis, genetic modification or structural modification and optimization of natural active ingredients. Second, this review provides a more detailed explanation of the anti-tumor mechanism of sinomenine and its derivatives and describes the study of alleviating tumor complications. Third, this review enriches the literature on the anti-tumor mechanism of sinomenine and its derivatives and adds to the understanding of the antitumor potential of sinomenine and its derivatives. Finally, this review collects and summarizes the relevant literature in the form of tables to facilitate reference by researchers in the field. Sinomenine is widely used in the treatment of rheumatism and joint pain because of its anti-inflammatory and analgesic effects, ability to remove wind dampness and ability to connect meridians. With the deepening of the study of its pharmacological properties, its anti-tumor value has been continuously explored. Moreover, the derivatives and nanocarriers of sinomenine resolve the problems of poor water solubility and low bioavailability. It is still necessary to improve the water solubility and bioavailability of sinomenine by using new technologies and new processes, such as drug synthesis, genetic modification or structural modification and optimization of natural active ingredients. Several studies of sinomenine have proven that sinomenine and its derivatives can not only promote tumor cell apoptosis and autophagy, and inhibit the proliferation, metastasis and invasion of tumor cells, but also enhance the chemo-and chemotherapy sensitivity of tumor cells and reverse the anti-tumor effect without increasing side effects (8,9,13,25). The anti-tumor mechanism of sinomenine is complex and plays a role in various pathways. Despite many studies, the main specific mechanism and targets of sinomenine anti-tumor, activity still need to be further explored through network pharmacology, and molecular docking combined with in vivo and in vitro experiments to lay a solid theoretical foundation for the clinical transformation of sinomenine and its derivatives as anti-tumor drugs. In conclusion, sinomenine and its derivatives have high anti-tumor potential and need to be further studied to promote their clinical development.

Acknowledgments

Funding: This work was supported by National Natural Science Foundation of China (Grant No. 82060477); Natural Science Foundation of Jiangxi Province (Grant No. 20202BAB206054); Science and Technology Plan of Jiangxi Provincial Health Commission in 2021 (No. 202120072); Nanchang Advantage science and technology Innovation team construction Plan project [Hongke Zi (2019) No. 228-15]; Nanchang high-level scientific and technological innovation talents “Double Hundred Plan “project [Hongke Zi (2021) No. 156-29]; General project of Traditional Chinese Medicine Science and Technology Plan of Jiangxi Province in 2021 (No. 2021B666); and Jiangxi Province Graduate Students Innovation Special Fund project in 2022 (No. YC2022-B069).

Footnote

Reporting Checklist: the authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-267/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-267/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-267/coif). The authors have no conflicts of interest to declare.

Ethical Statement: All authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. The global burden of adolescent and young adult cancer in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Oncol 2022;23:27-52. [Crossref] [PubMed]
2. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
3. Yamasaki H. Pharmacology of sinomenine, an anti-rheumatic alkaloid from Sinomenium acutum. Acta Med Okayama 1976;30:1-20. [PubMed]
4. Li RZ, Guan XX, Wang XR, et al. Sinomenine hydrochloride bidirectionally inhibits progression of tumor and autoimmune diseases by regulating AMPK pathway. Phytomedicine 2023;114:154751. [Crossref] [PubMed]
5. Zhu Z, Zhou H, Chen F, et al. Sinomenine Derivatives: Synthesis, Antitumor Activity, and Apoptotic Induction in MCF-7 Cells via IL-6/PI3K/Akt/NF-κB Signaling Pathway. ChemMedChem 2022;17:e202200234. [Crossref] [PubMed]
6. Fernández-García R, Lalatsa A, Statts L, et al. Transferosomes as nanocarriers for drugs across the skin: Quality by design from lab to industrial scale. Int J Pharm 2020;573:118817. [Crossref] [PubMed]
7. Wang Y, Zhao L, Yuan W, et al. A Natural Membrane Vesicle Exosome-based Sinomenine Delivery Platform for Hepatic Carcinoma Therapy. Curr Top Med Chem 2021;21:1224-34. [Crossref] [PubMed]
8. Duan D, Wang Y, Pan D, et al. Rheumatoid arthritis drug sinomenine induces apoptosis of cervical tumor cells by targeting thioredoxin reductase in vitro and in vivo. Bioorg Chem 2022;122:105711. [Crossref] [PubMed]
9. Li X, Chen W, Huang L, et al. Sinomenine hydrochloride suppresses the stemness of breast cancer stem cells by inhibiting Wnt signaling pathway through down-regulation of WNT10B. Pharmacol Res 2022;179:106222. [Crossref] [PubMed]
10. Song L, Tang L, Lu D, et al. Sinomenine Inhibits Vasculogenic Mimicry and Migration of Breast Cancer Side Population Cells via Regulating miR-340-5p/SIAH2 Axis. Biomed Res Int 2022;2022:4914005. [Crossref] [PubMed]
11. Zheng X, Li W, Xu H, et al. Sinomenine ester derivative inhibits glioblastoma by inducing mitochondria-dependent apoptosis and autophagy by PI3K/AKT/mTOR and AMPK/mTOR pathway. Acta Pharm Sin B 2021;11:3465-80. [Crossref] [PubMed]
12. Xu H, Dong J, Hou J, et al. Sinomenine Inhibits the Progression of Bladder Cancer Cells by Downregulating LncRNA-HEIH Expression. Evid Based Complement Alternat Med 2021;2021:4699529. [Crossref] [PubMed]
13. Cao J, Huang J, Gui S, et al. Preparation, Synergism, and Biocompatibility of in situ Liquid Crystals Loaded with Sinomenine and 5-Fluorouracil for Treatment of Liver Cancer. Int J Nanomedicine 2021;16:3725-39. [Crossref] [PubMed]
14. Bai S, Wen W, Hou X, et al. Inhibitory effect of sinomenine on lung cancer cells via negative regulation of alpha7 nicotinic acetylcholine receptor. J Leukoc Biol 2021;109:843-52. [Crossref] [PubMed]
15. Qu X, Yu B, Zhu M, et al. Sinomenine Inhibits the Growth of Ovarian Cancer Cells Through the Suppression of Mitosis by Down-Regulating the Expression and the Activity of CDK1. Onco Targets Ther 2021;14:823-34. [Crossref] [PubMed]
16. Song L, Zhang H, Hu M, et al. Sinomenine inhibits hypoxia induced breast cancer side population cells metastasis by PI3K/Akt/mTOR pathway. Bioorg Med Chem 2021;31:115986. [Crossref] [PubMed]
17. Shen KH, Hung JH, Liao YC, et al. Sinomenine Inhibits Migration and Invasion of Human Lung Cancer Cell through Downregulating Expression of miR-21 and MMPs. Int J Mol Sci 2020;21:3080. [Crossref] [PubMed]
18. Liu W, Yu X, Zhou L, et al. Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis. Onco Targets Ther 2020;13:3209-21. [Crossref] [PubMed]
19. Xu Y, Jiang T, Wang C, et al. Sinomenine hydrochloride exerts antitumor outcome in ovarian cancer cells by inhibition of long non-coding RNA HOST2 expression. Artif Cells Nanomed Biotechnol 2019;47:4131-8. [Crossref] [PubMed]
20. Gao G, Liang X, Ma W. Sinomenine restrains breast cancer cells proliferation, migration and invasion via modulation of miR-29/PDCD4 axis. Artif Cells Nanomed Biotechnol 2019;47:3839-46. [Crossref] [PubMed]
21. Zhang Y, Zou B, Tan Y, et al. Sinomenine inhibits osteolysis in breast cancer by reducing IL-8/CXCR1 and c-Fos/NFATc1 signaling. Pharmacol Res 2019;142:140-50. [Crossref] [PubMed]
22. Zhang D, Dong Y, Zhao Y, et al. Sinomenine hydrochloride sensitizes cervical cancer cells to ionizing radiation by impairing DNA damage response. Oncol Rep 2018;40:2886-95. [Crossref] [PubMed]
23. Song L, Liu D, Zhao Y, et al. Sinomenine reduces growth and metastasis of breast cancer cells and improves the survival of tumor-bearing mice through suppressing the SHh pathway. Biomed Pharmacother 2018;98:687-93. [Crossref] [PubMed]
24. Chen SP, Sun J, Zhou YQ, et al. Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models. Mol Pain 2018;14:1744806918793232. [Crossref] [PubMed]
25. Deng F, Ma YX, Liang L, et al. The pro-apoptosis effect of sinomenine in renal carcinoma via inducing autophagy through inactivating PI3K/AKT/mTOR pathway. Biomed Pharmacother 2018;97:1269-74. [Crossref] [PubMed]
26. Zhao B, Liu L, Mao J, et al. Sinomenine hydrochloride attenuates the proliferation, migration, invasiveness, angiogenesis and epithelial-mesenchymal transition of clear-cell renal cell carcinoma cells via targeting Smad in vitro. Biomed Pharmacother 2017;96:1036-44. [Crossref] [PubMed]
27. Li X, Li P, Liu C, et al. Sinomenine hydrochloride inhibits breast cancer metastasis by attenuating inflammation-related epithelial-mesenchymal transition and cancer stemness. Oncotarget 2017;8:13560-74. [Crossref] [PubMed]
28. Yang W, Feng Q, Li M, et al. Sinomenine Suppresses Development of Hepatocellular Carcinoma Cells via Inhibiting MARCH1 and AMPK/STAT3 Signaling Pathway. Front Mol Biosci 2021;8:684262. [Crossref] [PubMed]
29. Wang Y, Wu L, Cai H, et al. Sinomenine derivative YL064: a novel STAT3 inhibitor with promising anti-myeloma activity. Cell Death Dis 2018;9:1093. [Crossref] [PubMed]
30. Shen C, Li J, Li R, et al. Effects of Tumor-Derived DNA on CXCL12-CXCR4 and CCL21-CCR7 Axes of Hepatocellular Carcinoma Cells and the Regulation of Sinomenine Hydrochloride. Front Oncol 2022;12:901705. [Crossref] [PubMed]
31. Zhang JX, Yang ZR, Wu DD, et al. Suppressive effect of sinomenine combined with 5-fluorouracil on colon carcinoma cell growth. Asian Pac J Cancer Prev 2014;15:6737-43. [Crossref] [PubMed]
32. Liao F, Yang Z, Lu X, et al. Sinomenine sensitizes gastric cancer cells to 5-fluorouracil in vitro and in vivo. Oncol Lett 2013;6:1604-10. [Crossref] [PubMed]
33. Lu XL, Zeng J, Chen YL, et al. Sinomenine hydrochloride inhibits human hepatocellular carcinoma cell growth in vitro and in vivo: involvement of cell cycle arrest and apoptosis induction. Int J Oncol 2013;42:229-38. [Crossref] [PubMed]
34. Fu S, Jin L, Gong T, et al. Effect of sinomenine hydrochloride on radiosensitivity of esophageal squamous cell carcinoma cells. Oncol Rep 2018;39:1601-8. [Crossref] [PubMed]
35. He X, Maimaiti M, Jiao Y, et al. Sinomenine Induces G1-Phase Cell Cycle Arrest and Apoptosis in Malignant Glioma Cells Via Downregulation of Sirtuin 1 and Induction of p53 Acetylation. Technol Cancer Res Treat 2018;17:1533034618770305. [Crossref] [PubMed]
36. Chen SY, Zou Y, Huang YQ. Effects of Sinomenine on Proliferation and Apoptosis of MCL Jeko-1 Cell Line and Its Mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2017;25:1675-9. [PubMed]
37. Xie T, Ren HY, Lin HQ, et al. Sinomenine prevents metastasis of human osteosarcoma cells via S phase arrest and suppression of tumor-related neovascularization and osteolysis through the CXCR4-STAT3 pathway. Int J Oncol 2016;48:2098-112. [Crossref] [PubMed]
38. Wang J, Yang ZR, Dong WG, et al. Cooperative inhibitory effect of sinomenine combined with 5-fluorouracil on esophageal carcinoma. World J Gastroenterol 2013;19:8292-300. [Crossref] [PubMed]
39. Wang Y, Wu L, Cai H, et al. YL064 directly inhibits STAT3 activity to induce apoptosis of multiple myeloma cells. Cell Death Discov 2018;4:44. [Crossref] [PubMed]
40. Zhao A, Zhang J, Liu Y, et al. Synergic radiosensitization of sinomenine hydrochloride and radioiodine on human papillary thyroid carcinoma cells. Transl Oncol 2021;14:101172. [Crossref] [PubMed]
41. He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 2021;6:425. [Crossref] [PubMed]
42. Kwon JJ, Factora TD, Dey S, et al. A Systematic Review of miR-29 in Cancer. Mol Ther Oncolytics 2018;12:173-94. [Crossref] [PubMed]
43. Kim EM, Jung CH, Kim J, et al. The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins. Cancer Res 2017;77:3092-100. [Crossref] [PubMed]
44. Albadari N, Li W. Survivin Small Molecules Inhibitors: Recent Advances and Challenges. Molecules 2023;28:1376. [Crossref] [PubMed]
45. Chen J, Cheuk IWY, Shin VY, et al. Acetylcholine receptors: Key players in cancer development. Surg Oncol 2019;31:46-53. [Crossref] [PubMed]
46. Molist C, Navarro N, Giralt I, et al. miRNA-7 and miRNA-324-5p regulate alpha9-Integrin expression and exert anti-oncogenic effects in rhabdomyosarcoma. Cancer Lett 2020;477:49-59. [Crossref] [PubMed]
47. Zhang X, Zhang L, Chen M, et al. miR-324-5p inhibits gallbladder carcinoma cell metastatic behaviours by downregulation of transforming growth factor beta 2 expression. Artif Cells Nanomed Biotechnol 2020;48:315-24. [Crossref] [PubMed]
48. Gu C, Zhang M, Sun W, et al. Upregulation of miR-324-5p Inhibits Proliferation and Invasion of Colorectal Cancer Cells by Targeting ELAVL1. Oncol Res 2019;27:515-24. [Crossref] [PubMed]
49. Zheng Q, Zhu Q, Li C, et al. Sinomenine Can Inhibit the Growth and Invasion Ability of Retinoblastoma Cell through Regulating PI3K/AKT Signaling Pathway. Biol Pharm Bull 2020;43:1551-5. [Crossref] [PubMed]
50. Song L, Liu D, Zhao Y, et al. Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-kappaB activation mediated by IL-4/miR-324-5p/CUEDC2 axis. Biochem Biophys Res Commun 2015;464:705-10. [Crossref] [PubMed]
51. Hernandez GA, Perera RM. Autophagy in cancer cell remodeling and quality control. Mol Cell 2022;82:1514-27. [Crossref] [PubMed]
52. Liu Y, Liu C, Tan T, et al. Sinomenine sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway. Anticancer Drugs 2019;30:983-90. [Crossref] [PubMed]
53. Croucher PI, McDonald MM, Martin TJ. Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer 2016;16:373-86. [Crossref] [PubMed]
54. He L, Duan H, Li X, et al. Sinomenine down-regulates TLR4/TRAF6 expression and attenuates lipopolysaccharide-induced osteoclastogenesis and osteolysis. Eur J Pharmacol 2016;779:66-79. [Crossref] [PubMed]
55. Gao LN, Zhong B, Wang Y. Mechanism Underlying Antitumor Effects of Sinomenine. Chin J Integr Med 2019;25:873-8. [Crossref] [PubMed]