Efficacy and Safety of Compound Kushen Injection for Advanced Colorectal Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials with Trial Sequential Analysis.

BACKGROUNDS: Colorectal cancer (CRC) is one of the common malignant tumors, with a gradually increasing incidence. Due to late detection and poor sensitivity to chemotherapy, it has become a difficult problem in tumor prevention and treatment at present. Exploring or discovering new combinations is a significant strategy for the treatment of CRC. Compound kushen injection (CKI) is a traditional Chinese medicine injection extracted from Sophora flavescens Ait. and Smilax glabra Roxb., which is widely used in the comprehensive treatment of CRC in China. This systematic review is aimed to ascertain the clinical efficacy and safety of CKI combined with chemotherapy in the treatment of advanced CRC based on available data. On this basis, the specific application of CKI in combination with chemotherapy in clinical practice is further discussed. METHODS: PubMed, Web of Science, the Cochrane Library, EMBASE, China National Knowledge Infrastructure, Chinese Scientific Journals Database, Wanfang Database, Chinese Biomedicine Database Searches, the Chinese Clinical Trial Registry, and ClinicalTrials.gov were searched systematically, from inception to April 20, 2024. We adopted the ROB2 tool to assess quality of the included trials, Stata 16 for data analysis, and evaluated the publication bias with the funnel plot and Egger's test. The quality of the evidence was justified according to GRADE. We also used trial sequential analysis (TSA) to calculate the final required sample size in this meta-analysis and to verify whether the results present a reliable conclusion. The protocol for this systematic review was registered on PROSPERO (CRD42022380106) and has been published. RESULTS: Sixteen trials that examined 1378 patients were included in this study. Meta-analysis revealed that compared with chemotherapy, objective response rate (ORR, RR = 1.30, 95% CI: 1.18-1.44), disease control rate (DCR, RR = 1.08, 95% CI: 1.03-1.13), and KPS score improvement rate were improved (RR = 1.18, 95% CI: 1.07-1.31) by the combination of CKI and chemotherapy in patients with advanced CRC. Additionally, CKI combined with chemotherapy was associated with lower adverse reactions such as leukopenia (RR = 0.74, 95% CI: 0.62-0.87), thrombocytopenia (RR = 0.68, 95% CI: 0.49-0.94), gastrointestinal reactions (RR = 0.72, 95% CI: 0.55-0.94), and liver damage (RR = 0.48, 95% CI: 0.30-0.79), higher CD4+ ratio (MD = 9.70, 95% CI:8.73-10.68) and CD4+/CD8+ ratio (MD = 0.25, 95% CI: 0.22-0.28), and lower CD8+ T cell ratio (MD = -5.25, 95% CI: -5.94 to -4.56). Subgroup analysis demonstrated that ORR and DCR in patients with advanced CRC were improved when CKI combined with FOLFOX and 5Fu + L-OHP. Both 15 and 20 ml/day of CKI combined with FOLFOX provided a significant effect in ORR. Moreover, ORR was improved when the accumulated CKI dose reached 280 ml per course and 420 ml in total. 7 days/course as well as 14 days/course of CKI combined with FOLFOX were effective durations in ORR. As for DCR, 7 days/course of CKI combined with FOLFOX could improve efficacy. Furthermore, CKI + FOLFOX may be useful in ORR and DCR for at least 4 cycles of combination therapies. The TSA showed that firm results in ORR and DCR were established and additional trials were unlikely to change the results. CONCLUSION: CKI combined with chemotherapy provides a statistically significant and clinically important effect in the improvement of ORR, DCR, performance status, ADR reduction, and immune function in patients with CRC. However, more rigorously designed, large-scale, and multi-center RCTs are needed in the future.

[Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1].

Targeting p21-activated kinase 1 (PAK1) is a novel strategy for pancreatic cancer treatment. Compound Kushen injection contains many anti-pancreatic cancer components, but the specific targets are unknown. In this study, 14α-hydroxymatrine, an active component of Kushen injection, was found to possess high binding free energy with the allosteric site of PAK1 by molecular docking based virtual screening. Molecular dynamics simulations suggested that 14α-hydroxymatrine caused the α1 and α2 helices of the allosteric site of PAK1 to extend outward to form a deep allosteric regulatory pocket. Meanwhile, 14α-hydroxymatrine induced the ß-folding region at the adenosine triphosphate (ATP)-binding pocket of PAK1 to close inward, resulting in the ATP-binding pocket in a "semi-closed" state which caused the inactivation of PAK1. After removal of 14α-hydroxymatrine, PAK1 showed a tendency to change from the inactive conformation to the active conformation. We supposed that 14α-hydroxymatrine of compound Kushen injection might be a reversible allosteric inhibitor of PAK1. This study used modern technologies and methods to study the active components of traditional Chinese medicine, which laid a foundation for the development and utilization of natural products and the search for new treatments for pancreatic cancer.

The efficacy and safety of compound kushen injection for adults with esophageal cancer: A meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Kushen injection (CKI), derived from the traditional Chinese medicine Sophora flavescens, has been widely prescribed to treat a variety of cancers including esophageal cancer (ESCA) in China. AIM OF THE STUDY: This study aimed to evaluate the efficacy and safety of CKI for ESCA systematically. METHODS: The protocol was registered in the PROSPERO database with No. CRD42022320503. PubMed, Embase, the Cochrane Library, Web of Science, CNKI, Wanfang Database, Clinicaltrials, and Chi-CTR were searched to select RCTs that compared CKI with other interventions for ESCA with outcome measures including clinical efficacy, complete response, quality of life (QoL), adverse events (AEs), and serious AEs (SAEs). The Cochrane Risk of Bias 2 (RoB2) tool was used to assess the quality of RCT. The overall effect sizes were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) on binary outcome data. Meta-analyses were conducted to estimate effect sizes. Subgroup and sensitivity analyses on characteristics of RCTs were performed to test the robustness. Publication bias was also detected with different methods. The evidence strength was assessed with the Grading of Recommendation, Assessment, Development, and Evaluation method. RESULTS: This study finally included 35 RCTs with 2491 ESCA patients. The RoB of RCTs was some concern. The effect size of OR was 2.92 (95% CI [2.39, 3.57]) on clinical efficacy, 2.27 (95% CI [1.84, 2.81]) on complete response, 3.71 (95% CI [2.86, 4.80]) on QoL, 0.39 (95% CI [0.30, 0.50]) on AEs, and 0.13 (95% CI [0.07, 0.27]) on SAEs where the statistical significances (P < 0.00001) were found for all outcome measures. These overall effect sizes showed that CKI was more efficacious and safety for ESCA. Moreover, subgroup and sensitivity analyses found consistent results. Most publication bias analyses showed insignificant differences. The evidence strengths were moderate. CONCLUSION: The moderate evidence from this comprehensive PRISMA-compliant meta-analysis suggested that CKI may be a valuable alternative for adult patients with ESCA on its significant efficacy and safety. However, more RCTs of high quality with low RoB, large sample sizes, and long follow-up periods are still warranted to update the ESCA clinical guideline for physicians and policymakers in further study.

Compound Kushen injection combined with transarterial chemoembolization for hepatocellular carcinoma: An evidence map and overview of systematic reviews.

ETHNOPHARMACOLOGICAL RELEVANCE: For the treatment of hepatocellular carcinoma (HCC), compound Kushen injection (CKi) is commonly used in combination with transarterial chemoembolization (TACE). AIMS OF THE STUDY: Our objective was to evaluate the reporting quality, methodological quality, risk of bias, and certainty of evidence for CKi combined with TACE for the treatment of patients with HCC by conducting systematic reviews (SRs). The purpose of this study was to improve the clinical application of CKis, strengthen clinical decision-making regarding CKis, and inform future research. MATERIALS AND METHODS: We used eight databases to systematically search SRs of CKi combined with TACE for HCC through February 21, 2023. The quality of reporting of SRs was evaluated using the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, methodological quality using A MeaSurement Tool to Assess systematic Reviews 2, risk of bias using the Risk of Bias in Systematic Review, and certainty of evidence using the Grading of Recommendations Assessment. Finally, the assessment results were visualized by the evidence mapping method. This overview has been registered on PROSPERO with the registration title "Compound Kushen injection for hepatocellular carcinoma: An overview of systematic reviews" and registration number CRD42022369120. RESULTS: A total of 12 SRs meeting the inclusion criteria were included. In terms of reporting quality, 42% of SRs reported relatively complete reports and 58% had certain deficiencies. The methodological quality of all SRs was " critically low". The risk of bias was evaluated as low in 33% of SRs and high in 67% of SRs. The results of the evidence synthesis showed that, in the "moderate" level of evidence, CKi combined with TACE resulted in a 12.7%-21.5% benefit for one-year survival rate, 11.7%-17.2% benefit for objective response rate (ORR), 20.5%-27.1% benefit for quality of life, 22.2% benefit for nausea and vomiting, and 24.7%-27.4% benefit for leukopenia in HCC patients. CONCLUSION: In conclusion, CKi combined with TACE improved survival, ORR and quality of life in patients with HCC, and reduced adverse events. The results should be interpreted with caution due to the low methodological quality of the included SRs. The clinical efficacy of CKis must be confirmed in a large number of randomized controlled trials.

Clinical Effect of the Combination of Compound Kushen Injection and Gemcitabine on Postoperative Patients with Non-Muscle Invasive Bladder Cancer and Its Influence on Serum-Related Factors.

OBJECTIVE: To observe the clinical effect of the combination of compound Kushen injection (CKI) and gemcitabine on postoperative patients with non-muscular invasive bladder cancer (NMIBC) and its influence on serum-related factors. METHODS: A total of 150 patients with NMIBC were randomly divided into two groups. The patients in the control group (n = 75) received gemcitabine therapy; They were given 0.2 g gemcitabine once a week for 8 weeks after surgery and then changed to once every 2 weeks for eight times. The patients in the observation group (n = 75) were given CKI treatment on the basis of the control group for 10 days. The treatment was continued for three courses. After continuous follow-up for 2 years, the blood biochemistry, serum-related factors and immune T cell subsets and the safety and immune function changes, total effective rate, recurrence rate and occurrence of adverse reactions were evaluated. RESULTS: The interferon-γ, interleukin (IL)-2, clusters of differentiation (CD)8+, serum cell adhesion molecules (CAMs), hepatocyte CAM and cysteine proteinase-8 levels in the two groups after treatment significantly increased compared with those before treatment (p < 0.05), with the observation group showing more increase (p < 0.05). However, the tumour necrosis factor-α, C-reactive protein (CRP), IL-6, CD3+, CD4+, matrix metalloproteinase (MMP)-9, MMP-2, epithelial-specific CAM, soluble CAM-1, liver CAM, E-cadherin, vascular endothelial growth factor and fibroblast growth factor levels decreased significantly after treatment (p < 0.05), with the observation group exhibiting more decrease (p < 0.05). The adverse reactions and recurrence rate in the observation group obviously decreased in comparison to those in the control group (p < 0.05). CONCLUSIONS: The combination of CKI and gemcitabine can improve the inflammatory response, relieve the clinical symptoms of patients and reduce adverse clinical symptoms during gemcitabine infusion chemotherapy, with high safety.

Chinese herbal injections in combination with radiotherapy for advanced pancreatic cancer: A systematic review and network meta-analysis.

Background: Advanced pancreatic cancer (APC) is a fatal disease with limited treatment options. This study aims to evaluate the effectiveness and safety of different Chinese herbal injections (CHIs) as adjuvants for radiotherapy (RT) in APC and compare their treatment potentials using network meta-analysis. Methods: We systematically searched three English and four Chinese databases for randomized controlled trials (RCTs) from inception to July 25, 2023. The primary outcome was the objective response rate (ORR). Secondary outcomes included Karnofsky performance status (KPS) score, overall survival (OS), and adverse events (AEs). The treatment potentials of different CHIs were ranked using the surface under the cumulative ranking curve (SUCRA). The Cochrane RoB 2 tool and CINeMA were used for quality assessment and evidence grading. Results: Eighteen RCTs involving 1199 patients were included. Five CHIs were evaluated. Compound Kushen injection (CKI) combined with RT significantly improved ORR compared to RT alone (RR 1.49, 95 % CrI 1.21-1.86). Kanglaite (KLT) plus RT (RR 1.58, 95 % CrI 1.20-2.16) and CKI plus RT (RR 1.49, 95 % CrI 1.16-1.95) were associated with improved KPS score compared to radiation monotherapy, with KLT+RT being the highest rank (SUCRA 72.28 %). Regarding AEs, CKI plus RT was the most favorable in reducing the incidence of leukopenia (SUCRA 90.37 %) and nausea/vomiting (SUCRA 85.79 %). Conclusions: CKI may be the optimal choice of CHIs to combine with RT for APC as it may improve clinical response, quality of life, and reduce AEs. High-quality trials are necessary to establish a robust body of evidence. Protocol registration: PROSPERO, CRD42023396828.

Clinical Effect of the Combination of Compound Kushen Injection and Gemcitabine on Postoperative Patients with Non-Muscle Invasive Bladder Cancer and Its Influence on Serum-Related Factors

Objective: To observe the clinical effect of the combination of compound Kushen injection (CKI) and gemcitabine on postoperative patients with non-muscular invasive bladder cancer (NMIBC) and its influence on serum-related factors. Methods: A total of 150 patients with NMIBC were randomly divided into two groups. The patients in the control group (n = 75) received gemcitabine therapy; They were given 0.2 g gemcitabine once a week for 8 weeks after surgery and then changed to once every 2 weeks for eight times. The patients in the observation group (n = 75) were given CKI treatment on the basis of the control group for 10 days. The treatment was continued for three courses. After continuous follow-up for 2 years, the blood biochemistry, serum-related factors and immune T cell subsets and the safety and immune function changes, total effective rate, recurrence rate and occurrence of adverse reactions were evaluated. Results: The interferon-γ, interleukin (IL)-2, clusters of differentiation (CD)8+, serum cell adhesion molecules (CAMs), hepatocyte CAM and cysteine proteinase-8 levels in the two groups after treatment significantly increased compared with those before treatment (p < 0.05), with the observation group showing more increase (p < 0.05). However, the tumour necrosis factor-α, C-reactive protein (CRP), IL-6, CD3+, CD4+, matrix metalloproteinase (MMP)-9, MMP-2, epithelial-specific CAM, soluble CAM-1, liver CAM, E-cadherin, vascular endothelial growth factor and fibroblast growth factor levels decreased significantly after treatment (p < 0.05), with the observation group exhibiting more decrease (p < 0.05). The adverse reactions and recurrence rate in the observation group obviously decreased in comparison to those in the control group (p < 0.05) (AU)

Compound Kushen Injection Reduces Severe Toxicity and Symptom Burden Associated With Curative Radiotherapy in Patients With Lung Cancer.

BACKGROUND: Radiotherapy (RT) causes adverse events for which there are no effective treatments. This study investigated the clinical benefits of compound Kushen injection (CKI) in managing radiation injury in patients with lung cancer. METHODS: A multicenter, open-label, randomized clinical trial randomly assigned patients with lung cancer to receive either CKI (20 mL/d for at least 4 weeks) integrated with curative RT (RT + CKI group; n=130) or RT alone (control group; n=130). The primary outcome was the incidence of grade ≥2 radiation-induced lung injury (RILI) in the lungs, esophagus, or heart. Secondary outcomes included patient-reported symptoms, quality of life, objective response rate (ORR), and toxic effects. RESULTS: During the 16-week trial, the RT + CKI group had a significantly lower incidence of grade ≥2 RT-related injury than the control group (12.3% [n=16] vs 23.1% [n=30]; P=.02). Compared with the control group, the RT + CKI group experienced a significant decrease in moderate-to-severe symptoms of fatigue, cough, and pain (P<.001 for the treatment and time interaction term); significantly less physical symptom interference (P=.01); and significantly better quality of life by the end of the trial (P<.05). No statistically significant difference in ORR was found. Adverse reactions associated with CKI were rare. CONCLUSIONS: This study demonstrated low toxicity of CKI and its effectiveness in patients with lung cancer in reducing the incidence of grade ≥2 RILI and symptom burden, improving patients' quality of life.

Compound Kushen Injection inhibits epithelial-mesenchymal transition of gastric carcinoma by regulating VCAM1 induced by the TNF signaling pathway.

BACKGROUND: Gastric carcinoma (GC) treatment needs to be developed rapidly. Compound Kushen Injection (CKI), a formula from traditional Chinese medicine, has been used clinically in combination with chemotherapy to treat GC with satisfactory results. However, the molecular mechanism by which CKI acts to cure GC is still unclear. METHODS: In the present study, in vivo and in vitro experiments were used to assess the efficacy of CKI. Using ceRNA microarray and TMT technologies, the molecular mechanism of CKI was further investigated at the transcriptional and protein levels, and a bioinformatics approach was employed to investigate and functionally validate key CKI targets in GC. RESULTS: When combined with cisplatin (DDP), CKI significantly increased its efficacy in preventing the proliferation and metastasis of GC cells and malignant-looking tumors in mice. High-throughput sequencing data and bioinformatics analysis showed that CKI regulated the TNF signaling pathway, epithelial-mesenchymal transition (EMT), with VCAM1 as a key target. The transcription factors CEBPB, JUN, RELA, NFKB1, the EMT mesenchymal-like cell markers N-cadherin and vimentin, as well as the expression of VCAM1 and its upstream signaling driver TNF, were all downregulated by CKI. In contrast, the expression of the EMT epithelial-like cell marker E-cadherin was upregulated. CONCLUSION: CKI can effectively inhibit GC growth and metastasis, improve body's immunity, and protect normal tissues from damage. The molecular mechanism by which CKI inhibits metastasis of GC is by regulating VCAM1 induced by the TNF signaling pathway to inhibit EMT of GC. Our results provide an important clue to clarify precisely the multi-scale molecular mechanism of CKI in the treatment of GC.

Adjunctive effect of compound Kushen injection for cancer: An overview of systematic reviews.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Kushen (Sophora flavescens Aiton) Injection (CKI) is a Chinese herbal injection made from extracts of Kushen and Baituling (Heterosmilax japonica Kunth), containing matrine (MAT), oxymatrine (OMT) and other alkaloids with significant anti-tumor activity, and is widely used as an adjuvant treatment for cancer in China. AIM OF THE STUDY: The existing systematic reviews/meta-analyses (SRs/MAs) were re-evaluated to provide a reference for the clinical application of CKI. MATERIALS AND METHODS: SRs/MAs of CKI adjuvant therapy for cancer-related diseases were searched in four English language databases: PubMed, Embase, Web of Science, and Cochrane Library, all from the time of database construction to October 2022. 5 researchers independently conducted literature search and identification according to the inclusion criteria, and the data of the final literature were independently extracted, and finally the AMSTAR 2 tool, PRISMA statement and GRADE classification were used to evaluate the methodological quality of the included SRs/MAs, the degree of completeness of reporting and the quality of evidence for outcome indicators. Database registration: PROSPERO ID：CRD42022361349. RESULTS: Eighteen SRs/MAs were finally included, with studies covering non-small cell lung cancer, primary liver cancer, gastric cancer, colorectal cancer, breast cancer, head and neck tumors, and cancer-related bone pain. The evaluation showed that the methodological quality of the included literature was extremely low, but most of the literature reported relatively complete entries; nine clinical effectiveness indicators for non-small cell lung cancer and digestive system tumors were rated as moderate in the GRADE quality of evidence, and the quality of other outcomes was low to very low. CONCLUSION: CKI is a potentially effective drug for the adjuvant treatment of neoplastic diseases and may be more convincing for the adjuvant treatment of non-small cell lung cancer and digestive system tumors; however, due to the low methodological and evidentiary quality of the current SRs, their effectiveness needs to be confirmed by more high-quality evidence-based medical evidence.

An integrated analytical strategy to decipher the metabolic profile of alkaloids in Compound Kushen injection based on UHPLC-ESI-QTOF/MSE.

Compound Kushen injection (CKI) is a kind of sterilised water-soluble traditional Chinese medicine preparation that has been used for the clinical treatment of a variety of cancers (hepatocellular carcinoma, lung cancer, etc.) for 19 years. However, to date, the metabolism-related study on CKI in vivo has not been conducted.An integrated analytical strategy was established to investigate the metabolic profile of alkaloids of CKI in rat plasma, urine, and faeces based on ultra-high performance liquid chromatography-electrospray quadrupole time-of-flight mass spectrometry in MSE mode (UHPLC-ESI-QTOF/MSE).Nineteen prototype alkaloids (including 12 matrine-type alkaloids, 2 cytisine-type alkaloids, 3 lupinine-type alkaloids, and 2 aloperine-type alkaloids) of CKI were identified in vivo. Furthermore, 71 metabolites of alkaloids (including 11 of lupanine-related metabolites, 14 of sophoridine-related metabolites, 14 of lamprolobine-related metabolites, and 32 of baptifoline-related metabolites) were tentatively characterised. Metabolic pathways involved in the metabolism of phase I (include oxidation, reduction, hydrolysis, and desaturation), phase II (mainly include glucuronidation, acetylcysteine or cysteine conjugation, methylation, acetylation, and sulphation), and associated combination reactions.The integrated analytical strategy was successfully used to characterise the prototype alkaloids and their metabolites of CKI in vivo, and the results laying a foundation for further study its pharmacodynamic substances.

Elucidating the pharmacological effects of Compound Kushen injection on MYC-P15-CCND1 signaling pathway in nasopharyngeal carcinoma - An in vitro study.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Kushen injection (CKI) is a representative medication of Chinese herbal injection and is often used in the adjuvant treatment of nasopharyngeal carcinoma (NPC), but its antitumor mechanism is poorly understood. AIM OF THE STUDY: To preliminarily elucidate the effects and possible mechanisms of CKI on NPC. METHODS: In this work, we explored the possible molecular mechanisms of CKI against NPC by using network pharmacology and molecular docking. In addition, proteomics was used to explore the localization and quantitative information of protein in NPC C666-1 cells after the intervention of CKI, and enrichment analysis was used to obtain the potential targets and pathways. Finally, the effect and the core targets of CKI in the intervention of NPC were explored in vitro experiments. RESULTS: Network pharmacology analysis identified three active components of CKI and 13 key targets. Molecular docking analysis showed that TNF, PTEN, CCND1, MAPK3, IL6, HIF1A, MYC had high affinity with corresponding components. Then the key pathway, cell cycle and the core targets MYC, CCND1, and P15 related to the key pathway were obtained. The results of in vitro experiments showed that CKI could inhibit the proliferation, migration, and invasion of NPC 5-8F cells and C666-1 cells, induce apoptosis of C666-1 cells, and arrest cell cycle G0/G1 phase. In addition, RT-qPCR and western blot showed that the expression of P15 was up-regulated and E2F4, E2F5, c-Myc, CCND1, and P107 was down-regulated in 5-8F cells and C666-1 cells intervened by CKI. CONCLUSION: The key pathway, cell cycle and the corresponding core targets MYC, CCND1, and P15 were obtained from network pharmacology, molecular docking, and proteomics. CKI could inhibit the proliferation, migration, and invasion of NPC cells, induce apoptosis of C666-1 cells. Especially CKI may arrest cell cycle G0/G1 phase through regulating targets MYC/P15/CCND1 of cell cycle pathway.

Evaluation of efficacy and safety for compound kushen injection combined with intraperitoneal chemotherapy for patients with malignant ascites: A systematic review and meta-analysis.

Objectives: Compound Kushen injection (CKI) combined with intraperitoneal chemotherapy (IPC) is widely used in the treatment of malignant ascites (MA). However, evidence about its efficacy and safety remains limited. This review aimed to evaluate the efficacy and safety of CKI combined with IPC for the treatment of MA. Methods: Protocol of this review was registered in PROSPERO (CRD42022304259). Randomized controlled trials (RCTs) on the efficacy and safety of IPC with CKI for the treatment of patients with MA were searched through 12 electronic databases and 2 clinical trials registration platforms from inception until 20 January 2023. The Cochrane risk-of-bias tool was used to assess the quality of the included trials through the risk of bias assessment. We included RCTs that compared IPC single used or CKI combined with IPC for patients with MA schedule to start IPC. The primary outcome was identified as an objective response rate (ORR), while the secondary outcomes were identified as the quality of life (QoL), survival time, immune functions, and adverse drug reactions (ADRs). The Revman5.4 and Stata17 software were used to calculate the risk ratio (RR) at 95% confidence intervals (CI) for binary outcomes and the mean difference (MD) at 95% CI for continuous outcomes. The certainty of the evidence was assessed according to the GRADE criteria. Results: A total of 17 RCTs were assessed, which included 1200 patients. The risk of bias assessment of the Cochrane risk-of-bias tool revealed that one study was rated high risk and the remaining as unclear or low risk. Meta-analysis revealed that CKI combined with IPC had an advantage in increasing ORR (RR = 1.31, 95% CI 1.20 to 1.43, p < 0.00001) and QoL (RR = 1.50, 95% CI 1.23 to 1.83, p < 0.0001) when compared with IPC alone. Moreover, the combined treatment group showed a lower incidence of myelosuppression (RR = 0.51, 95%CI 0.40-0.64, p < 0.00001), liver dysfunction (RR = 0.33, 95%CI 0.16 to 0.70, p = 0.004), renal dysfunction (RR = 0.39, 95%CI 0.17 to 0.89, p = 0.02), and fever (RR = 0.51, 95%CI 0.35 to 0.75, p = 0.0007) compared to those of the control group. The quality of evidence assessment through GRADE criteria showed that ORR, myelosuppression, and fever were rated moderate, renal dysfunction and liver dysfunction were rated low, and QoL and abdominal pain were rated very low. Conclusion: The efficacy and safety of CKI combined with IPC were superior to that with IPC alone for the treatment of MA, which indicates the potentiality of the treatment. However, more high-quality RCTs are required to validate this conclusion. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022304259], identifier [PROSPERO 2022 CRD42022304259].

Downregulation of PRMT5 by AMI-1 enhances therapeutic efficacy of compound kushen injection in lung carcinoma in vitro and in vivo.

Protein arginine methyltransferase 5 (PRMT5) is overexpressed in lung carcinoma, which promotes tumor cell proliferation, survival, migration and invasion. Compound Kushen injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling, which are mainly used to stop in cancer pain and bleeding. Here we found that cell viability and colony formation were inhibited after the incubation of AMI-1. Meanwhile, AMI-1 suppressed cell migration, enhanced apoptosis, induced cell cycle arrest, inhibited PRMT5 expression and histone H3R8 and H4R3 symmetric di-methylation (H3R8me2s and H4R3me2s) accumulation, down-regulated the expression of eukaryotic translation initiation factor 4E (eIF4E) in lung carcinoma cells. Moreover, AMI-1 suppressed tumor growth, decreased H3R8me2s and H4R3me2s accumulation, down-regulated eIF4E expression and increased p53 expression in lung carcinoma xenografts of BALB/c nude mice. Of note, combined and CKI markedly enhanced the anticancer efficacy CKI in lung carcinoma. The above findings demonstrated that AMI-1 has established antineoplastic activity and this role may be associated with affecting the function of eIF4E via inhibiting PRMT5 activity or protein levels in lung carcinoma. This study highlights evidence of novel selective anticancer activity of AMI-1 in combination with CKI in lung carcinoma.

Mechanism of compound kushen injection in the treatment of lung cancer based on serum metabolomics and network pharmacology / 中国临床药理学与治疗学

AIM: To explore the mechanism of action of alkaloid components of compound kushen Injection (CKI) in the treatment of lung cancer based on serum metabolomics, network pharmacology, and molecular docking techniques. METHODS: A lung cancer model was established in C57 mice by inoculation of Lewis mouse lung cancer tumor strain. Thirty male mice were randomly divided into normal group, model group and CKI group. The drug was administered by tail vein injection once daily for 17 consecutive days. Mouse serum was examined by ultrahigh performance liquid chromatography tandem mass spectrometry (LC-MS) metabolomics, and several multivariate statistical analyses including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), combined with databases such as the human metabolic database (HMDB) and related literature to identify and identify differential metabolites, the relevant metabolic pathways were searched for by the metaboanalyst online tool. Using network pharmacology, construct the“component-target-disease”network of CKI in the treatment of lung cancer. Molecular docking method was used to verify the interaction between potential active ingredients and core targets. Serum metabolomics was jointly analyzed with network pharmacology to construct a“metabolite-germinal-enzyme-gene” network. RESULTS: Through metabolomics technology, 16 differential metabolites associated with lung cancer were screened from serum, and CKI addback these differential metabolite levels compared with the model group. Metabolic pathways mainly involve retinol metabolism, tryptophan metabolism, glycerophospholipid metabolism and other metabolic pathways. Network pharmacology analysis indicated that CKI treatment of lung cancer mainly targets STAT3, MAPK3, and MAPK1, which are closely related to proteoglycans, cellular senescence, and HIF − 1 signaling pathways in cancer. CONCLUSION: This article explains the mechanism of CKI in treating lung cancer from the perspective of metabonomics and network pharmacology, and provides basis for further study of CKI.

Clinical efficacy of Compound Kushen Injection combined with SOX regimen in the treatment of elderly patients with advanced gastric cancer / 国际肿瘤学杂志

Objective:To explore the clinical efficacy and influence on quality of life of Compound Kunshen Injection combined with SOX regimen (Tigio + Oxaliplatin) in the treatment of elderly patients with advanced gastric cancer.Methods:A total of 76 elderly patients with advanced gastric cancer admitted to Caidian District People's Hospital of Wuhan from May 2017 to December 2021 were retrospectively analyzed. Patients were divided into study group ( n=38) and control group ( n=38) according to different treatment methods. The study group was treated with Compound Kunshen Injection combined with SOX regimen, and the control group was treated with SOX regimen. All patients received at least 2 cycles of chemotherapy. The disease control rate (DCR) , the changes of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) before and after treatment of the two groups were compared. The occurrence of adverse reactions to chemotherapy and the improvement of quality of life related indicators before and after treatment were observed in the two groups. Results:The DCR of the study group was 84.2% (32/38) and that of the control group was 63.2% (24/38) , with a statistically significant difference ( χ2=4.34, P=0.037) . After treatment, CEA levels in both study group and control group were decreased compared with those before treatment [7.92 (5.00, 50.23) ng/ml vs. 40.08 (6.37, 68.18) ng/ml, Z=3.53, P<0.001; 40.24 (20.12, 53.69) ng/ml vs. 41.32 (11.50, 63.90) ng/ml, Z=2.06, P=0.044], and CEA level in the study group was decreased more significantly than that in the control group ( Z=1.99, P=0.048) . After treatment, CA199 levels in both study group and control group were decreased compared with those before treatment [20.23 (17.34, 71.31) U/ml vs. 70.14 (12.75, 96.95) U/ml, Z=2.70, P=0.007; 54.25 (30.54, 76.75) U/ml vs. 62.28 (23.00, 84.80) U/ml, Z=2.37, P=0.018], with no statistically significant difference in the reduction level of CA199 between the two groups ( Z=0.73, P=0.463) . Most of the adverse reactions in the two groups during chemotherapy were grade 1-2, which disappeared after symptomatic treatment. Compared with the control group, the study group had lower incidence of gastrointestinal reaction [26.3% (10/38) vs. 52.6% (20/38) , χ2=5.50, P=0.019], myelosuppression [18.4% (7/38) vs. 44.7% (17/38) , χ2=6.09, P=0.014] and peripheral neurotoxicity [21.1% (8/38) vs. 44.7% (17/38) , χ2=4.83, P=0.028]. The improvements of QOL score [78.9% (30/38) vs. 55.3% (21/38) , χ2=4.83, P=0.028], Karnofsky performance status score [71.1% (27/38) vs. 47.4% (18/38) , χ2=4.41, P=0.036], hemoglobin [73.7% (28/38) vs. 50.0% (19/38) , χ2=4.52, P=0.034] and pain control [65.8% (25/38) vs. 24.1% (16/38) , χ2=4.29, P=0.038] of the study group were better than those of the control group, with statistically significant differences. Conclusion:Compound Kunshen Injection combined with SOX regimen in the treatment of elderly patients with advanced gastric cancer can not only improve the DCR of patients, but also reduce the serum levels of tumor markers CEA and CA199, among which the CEA decline is more obvious, reduce the incidence of adverse reactions of chemotherapy and improve the quality of life of patients.

Single-cell RNA-sequencing uncovers compound kushen injection synergistically improves the efficacy of chemotherapy by modulating the tumor environment of breast cancer.

Background: Due to lack of enough specific targets and the immunosuppressive tumor microenvironment (TME) of triple-negative breast cancer (TNBC), TNBC patients often cannot benefit from a single treatment option. This study aims to explore the regulatory effects of Compound kushen injection (CKI) plus chemotherapy on the TME of TNBC from a single cell level. Methods: A mouse TNBC model in BALB/c mice was established to evaluate the antitumor efficacy and toxicity of CKI combined with chemotherapy. Flow cytometry was used to observe the influence of CKI on the lymphocyte populations in the tumor bearing mice. Both bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) were applied to portray the modulation of CKI combined with chemotherapy on the TME of TNBC mice. Results: CKI significantly enhanced the anticancer activity of chemotherapy in vivo with no obvious side effects. Flow cytometry results revealed a significantly higher activation of CD8+ T lymphocytes in the spleens and tumors of the mice with combination therapy. Bulk RNA-seq indicated that CKI could promote the cytotoxic immune cell infiltrating into tumor tissues. Meanwhile, scRNA-seq further revealed that CKI combined with chemotherapy could enhance the percentage of tumor-infiltrating CD8+ T cells, inhibit tumor-promoting signaling pathways, and promote T cell activation and positive regulation of immune response. In addition, CKI showed obvious anticancer activity against MDA-MB-231 breast tumor cells in vitro. Conclusions: The combination of CKI and chemotherapy might provide a higher efficiency and lower toxicity strategy than a single chemotherapy drug for TNBC. CKI potentiates the anti-TNBC effects of chemotherapy by activating anti-tumor immune response in mice.

Exploring the nucleotide molecular mechanism of compound kushen injection for lung adenocarcinoma based on network pharmacology and molecular docking.

Compound kushen injection is an effective traditional Chinese medicine for the treatment of lung cancer. However, its influence on the survival and prognosis of patients with lung adenocarcinoma patients was less studied; especially its pharmacological mechanism remains to be further elucidated. In the present study, we adopted a network pharmacology (NP)-based approach to screening effective compounds, screening and predicting target genes, analyzing biological functions and pathways, constructing a regulatory network and protein interaction network, and screening the key targets. Moreover, mass survival analysis and molecular docking were conducted. In the end, 35 key compounds and four possible central target genes were screened out, which could be used for the treatment of lung adenocarcinoma and affected the survival and prognosis of patients with lung adenocarcinoma. In addition, their key compounds had good docking affinity. Enrichment analysis showed that CKI might affect the treatment and prognosis of lung adenocarcinoma patients by regulating the PI3K-Akt signaling pathway, TNF signaling pathway, non-small cell lung cancer, Hepatitis C, etc. We discussed the pharmacological mechanisms and potential therapeutic targets of CKI in the treatment of lung adenocarcinoma, which verified the effect of CKI on the prognosis and survival of patients. The present study might promote the further clinical application of CKI and provide a theoretical basis for further experimental studies.

Compound Kushen injection reduces severity of radiation-induced gastrointestinal mucositis in rats.

Mucositis, or damage/injury to mucous membranes of the alimentary, respiratory, or genitourinary tract, is the major side effect associated with anticancer radiotherapies. Because there is no effective treatment for mucositis at present, this is a particular issue as it limits the dose of therapy in cancer patients and significantly affects their quality of life. Gastrointestinal mucositis (GIM) occurs in patients receiving radiotherapies to treat cancers of the stomach, abdomen, and pelvis. It involves inflammation and ulceration of the gastrointestinal (GI) tract causing diarrhea, nausea and vomiting, abdominal pain, and bloating. However, there is currently no effective treatment for this debilitating condition. In this study, we investigated the potential of a type of traditional Chinese medicine (TCM), compound Kushen injection (CKI), as a treatment for GIM. It has previously been shown that major groups of chemical compounds found in CKI have anti-inflammatory effects and are capable of inhibiting the expression of pro-inflammatory cytokines. Intraperitoneal administration of CKI to Sprague Dawley (SD) rats that concurrently received abdominal irradiation over five fractions resulted in reduced severity of GIM symptoms compared to rats administered a vehicle control. Histological examination of the intestinal tissues revealed significantly less damaged villus epithelium in CKI-administered rats that had reduced numbers of apoptotic cells in the crypts. Furthermore, it was also found that CKI treatment led to decreased levels of inflammatory factors including lower levels of interleukin (IL)-1ß and IL-6 as well as myeloperoxidase (MPO)-producing cells in the intestinal mucosa. Together, our data indicate a novel effect of CKI to reduce the symptoms of radiation-induced GIM by inhibiting inflammation in the mucosa and apoptosis of epithelial cells.

Exploring the pharmacological mechanism of compound kushen injection in the treatment of breast cancer using in vitro experiments: Coupling network pharmacology with GEO database.

Background: Breast cancer (BC) is one of the most common malignant tumors in women and poses a serious threat to their health. Compound Kushen injection (CKI) has shown therapeutic effects on a variety of cancers, including BC, and it can significantly improve the lives of patients. However, the underlying mechanism remains unclear and needs to be fully elucidated. Methods: The active constituents of CKI were identified through a literature review, and the anti-BC targets of CKI were determined using multiple databases and a ChIP data analysis. Subsequently, the target was analyzed on the DAVID database through GO and KEGG to identify the key pathway that CKI affects to exhibit anti-BC activity. In addition, MCF-7 and MDA-MB-231 cells were treated with CKI for 24 and 48 hours at five concentrations, and the effects of CKI on cell proliferation and apoptosis were measured using MTT and annexin V/propidium iodide staining assays, respectively. The genes and protein identified to be involved in this pathway were verified using real-time quantitative PCR (qPCR) and western blot(WB) in BC cells. Results: Twelve CKI anti-BC targets were obtained by a comprehensive analysis of the targets collected in the databases and results from the ChIP analysis. Bioinformatics analysis was performed for 12 targets. KEGG analysis showed that the 12 targets were mainly related to the VEGF, ErbB, and TNF signaling pathways. We focused our study on the VEGF signaling pathway as the p-value for the VEGF signaling pathway was the lowest among the three pathways. In vitro experiments showed that CKI significantly inhibited the proliferation of BC cells and induced apoptosis. Furthermore, qPCR and WB experiments showed that the expression of VEGF signaling pathway genes PIK3CA and NOS3 were significantly increased meanwhile SRC was significantly decreased after CKI intervention. Conclusion: CKI significantly inhibited the proliferation of BC cells and induced apoptosis. The main mechanism for the anti-BC effect of CKI may be that it regulates the VEGF signaling pathway by increasing the expression of PIK3CA, SRC, and NOS3. Macrozamin and lamprolobine may be the main active components of CKI against BC.