A pilot study of precision treatment for patients with lung cancer pain by Longteng Tongluo recipe (龙藤通络方) using serum genomics

  • Ruixin WU ,
  • Qingliang FANG ,
  • Sisi GUAN ,
  • Xianglong WEI ,
  • Mengjun SHAN ,
  • Zhujun MAO ,
  • Yabin GONG ,
  • Ling XU ,
  • Di ZHOU ,
  • Changsheng DONG
Expand
  • 1 Preclinical Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
    2 School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
    3 Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    4 Department of Oncology, the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450003, China
    5 Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
    6 Cancer Institute of Traditional Chinese Medicine/Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China

Received date: 2023-07-22

  Accepted date: 2023-12-05

  Online published: 2024-09-11

Supported by

a Multicenter Randomized Controlled Clinical Study of Longteng Tongluo Recipe for the Treatment of Lung Cancer Pain(202040155);Study The Mechanism of Longteng Tongluo Recipe in Cancer Pain based on The Theory of Tonifying Yuan Qi and Detoxification(RC-2017-02-02);External Treatment of Cancer Pain of Traditional Chinese Medicine to Promote Percutaneous Absorption of Ultrasound Instrument(20S31904100);Shanghai Clinical Research Center of Traditional Chinese Medicine Oncology(21MC1930500);Discussion on the Anti-apoptotic Effect of Qidongning Prescription on Lung Cancer Based on Energy Metabolismin Disorder of Mitochondria(2021yygq05)

Abstract

OBJECTIVE: To investigate the efficacy of Longteng Tongluo recipe (龙藤通络方, LTTL) combined with three-step analgesia for the treatment of lung cancer pain, and the changes in serum miRNA expressions before- and after treatment with LTTL and its correlation with lung cancer pain. The possible mechanism underlying LTTL effects on the treatment of lung cancer pain was conducted.

METHODS: The pilot study was conducted at the oncology ward of the Yueyang Hospital and the Longhua Hospital between March 2018 and October 2019. A prospective, single-blind, placebo controlled, randomized clinical trial of LTTL or placebo combined with three-step analgesia treatments were administered to 24 cancer pain patients diagnosed with lung cancer. Analgesic efficacy was investigated as the primary outcome. Equivalent morphine consumption and numerical rating scale (NRS) scores were used as the secondary outcome. In the present study, we utilized deep sequencing techniques to compare the differential miRNA expressions in serum samples obtained from two groups: the lung cancer pain treatment group (LTTL + three-step analgesia) and the control group (placebo + three-step analgesia). Next, we employed the target prediction database to investigate the target genes for differential miRNA expressions and Gene Ontology (GO) analysis along with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to examine the roles and the major biochemical and signaling pathways related to the differentially expressed target genes, respectively.

RESULTS: LTTL treatment significantly reduces the NRS score (P = 0.021) as compared to those before treatment, along with significant reductions in the total morphine equivalent consumption (P = 0.007) and the average daily equivalent morphine consumption (P = 0.003) as opposed to the control group. The expressions of 31 miRNAs differed considerably between the two groups of patients (≥ 2 times up-modulated or down-regulated between these groups, P<0.05). For instance, the miRNAs expression levels for patients before treatment (has-miR-2110 and has-miR-7d-3p) were significantly enhanced as compared to the healthy people, after LTTL treatment, the expressions of miR-2110 and miR-7d-3p in patients with lung cancer pain reduced significantly. Studies show that the above two miRNAs were significantly associated with lung cancer pain, which could mediate lung cancer pain. Furthermore, we identified 355 genes as potential targets of the 31 differentially expressed miRNAs. Pathway enrichment analyses using KEGG and GO analysis indicated that these target genes may play a crucial role in the development and modulation of lung cancer pain.

CONCLUSION: LTTL demonstrated a discernible impact on alleviating lung cancer pain and its mechanism of action may be related to the downregulation of has-miR-2110 and has-miR-7d-3p expressions. This pilot study provides support for further exploration of LTTL in patients with lung cancer pain.

Cite this article

Ruixin WU , Qingliang FANG , Sisi GUAN , Xianglong WEI , Mengjun SHAN , Zhujun MAO , Yabin GONG , Ling XU , Di ZHOU , Changsheng DONG . A pilot study of precision treatment for patients with lung cancer pain by Longteng Tongluo recipe (龙藤通络方) using serum genomics[J]. Journal of Traditional Chinese Medicine, 2024 , 44(5) : 1006 -1016 . DOI: 10.19852/j.cnki.jtcm.20240828.005

References

1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023; 73: 17-48.
2. Zheng RS, Zhang SW, Sun KX, et al. Cancer statistics in China, 2016. Zhong Hua Zhong Liu Za Zhi 2023; 45: 212-20.
3. He YH, Guo XF, Brian HM, et al. Clinical evidence for Association of acupuncture and acupressure with improved cancer pain: a systematic review and Meta-analysis. JAMA Oncol 2020; 6: 271-8.
4. Van D, Rijke JD, Kessels A, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18: 1437-49.
5. Bollen L, Wibmer C, Van der Linden YM, et al. Predictive value of six prognostic scoring systems for spinal bone metastases, an analysis based on 1379 patinets. Spine 2016; 41: 155-62.
6. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006; 12: 6243s-49s.
7. Nielsen OS, Munro AJ, Tannock IF. Bone metastases: pathophysiology and management policy. J Clin Oncol 1991; 509-24.
8. Honore P, Luger NM, Sabino MAC, et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction. skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 2000; 6: 521-8.
9. Scarborough BM, Smith CB. Optimal pain management for patients with cancer in the modern era. CA Cancer J Clin 2018; 68: 182-96.
10. Pachman DR, Barton DL, Swetz KM, Loprinzi CL. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J Clin Oncol 2012; 30: 3687-96.
11. Swarm RA, Paice JA, Anghelescu DL, et al. Adult cancer pain, Version 3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2019; 17: 977-1007.
12. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines), adult cancer pain. online, 2018-1-22, published, 2018-6-10, version 1. Available from URL: https://www.nccn.org/professionals/default.aspx.
13. Deng G. Integrative medicine therapies for pain management in cancer patients. Cancer J 2019; 25: 343-8.
14. Johns JR, Williams G, Pazdur R. End points and united states food and drug administration approval of oncology drugs. J Clin Oncol 2003; 21: 1401-11.
15. Lee J, Yoon SW. Efficacy and safety of moxibustion for relieving pain in patients with metastatic cancer: a pilot, randomized, single-blind, sham-controlled trial. Integr Cancer Ther 2014; 13: 211-16.
16. Wang YH, Chang JY, Feng L. Effect of oral Chinese medicine combined with Western Medicine on cancer pain: a Meta-analysis. Integr Cancer Ther 2021; 27: 713-20.
17. Wang JY, Zhang RX, Dong CS, et al. Transient receptor potential channel and interleukin-17A involvement in LTTL gel inhibition of bone cancer pain in a rat model. Integr Cancer Ther 2015; 14: 381-93.
18. Wang JY, Zhang RX, Dong CS, et al. Topic treatment of Tong-Luo-San-Jie gel alleviates bone cancer pain in rats. J Ethnopharmacol 2012; 143: 905-13.
19. Liu CY. Chinese Herbal Medicine:Modern applications of traditional formulas. Carabas. Florida: Chemical & Rubber & Company Press, 2004: 16.
20. Ilfeld BM, Plunkett A, Vijjeswarapu AM, et al. Percutaneous peripheral nerve stimulation (neuromodulation) for postoperative pain: a randomized, sham-controlled pilot study. Anesthesiology 2021; 135: 95-110.
21. Langmead B, Trapnell C, Pop M, et al. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 2009; 10: 25-34.
22. Nawrocki EP, Eddy SR. Infernal 1.1: 100-fold faster RNA homology searches. Bioinformatics 2013; 29: 2933-5.
23. Friedl?nder MR, Chen W, Adamidi C, et al. Discovering microRNAs from deep sequencing data using miRDeep. Nat Biotechnol 2008; 26: 407-15.
24. Wang K, Liang C, Liu J, et al. Prediction of piRNAs using transposon interaction and a support vector machine. BMC Bioinformatics 2014; 15: 419.
25. Krüger J, Rehmsmeier M. RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Res 2006; 34: W451-4.
26. John B, Sander C, Marks DS. Prediction of human microRNA targets. Methods Mol Biol 2006; 342: 101-13.
27. Agarwal V, Bell GW, Nam J, et al. Predicting effective microRNA target sites in mammalian mRNAs. Elife 2015; 4: e05005.
28. Kivioja T, V?h?rautio A, Karlsson K, et al. Counting absolute numbers of molecules using unique molecular identifiers. Nat Methods 2011; 9: 72-4.
29. Wang L, Feng Z, Wang X, et al. DEGseq: an R package for identifying differentially expressed genes from RNA-seq data. Bioinformatics 2010; 26: 136-8.
30. Sheu MJ, Chou PY, Cheng HC, et al. Analgesic and anti-inflammatory activities of a water extract of trachelospermum jasminoides (apocynaceae). J Ethnopharmacol 2009; 126: 332-8.
31. Luo Y, Wang CZ, Sawadogo R, et al. Effects of herbal medicines on pain management. Am J Chin Med 2020; 48: 1-16.
32. Yuan CS, Mehendale SR, Wang CZ, et al. Effects of corydalis Yanhusuo and angelicae dahuricae on cold pressor-induced pain in humans: a controlled trial. J Clin Pharmacol 2004; 44: 1323-27.
33. Fan AY, Lao LX, Zhang RX, et al. Effects of an acetone extract of Boswellia Carterii Birdw (Burseraceae) gum resin on rats with persistent inflammation. J Altern Complement Med 2005; 11: 323-31.
34. Su S, Hua Y, Wang Y, et al. Evaluation of the anti-inflammatory and analgesic properties of individual and combined extracts from Commiphora Myrrha, and Boswellia Carterii. J Ethnopharmacol 2012; 139: 649-56.
35. Xie F, Zhang M, Zhang CF, et al. Anti-inflammatory and analgesic activities of ethanolic extract and two limonoids from melia toosendan fruit. J Ethnopharmacol 2008; 117: 463-6.
36. Zhang Y, Wang C, Wang L, et al. A novel analgesic isolated from a Traditional Chinese Medicine. Curr Biol 2014; 24: 117-23.
37. Ajit SK. Circulating microRNAs as biomarkers, therapeutic targets, and signaling molecules. Sensors (Basel) 2012; 12: 3359-69.
38. Aguado Fraile E, Ramos E, Conde E, et al. MicroRNAs in the kidney: novel biomarkers of acute kidney injury. Nefrologia 2013; 33: 826-34.
39. Chen YH, Heneidi S, Lee JM, et al. miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes 2013; 62: 2278-86.
40. Elramah S, López González MJ, Bastide M, et al. Spinal miRNA-124 regulates synaptopodin and nociception in an animal model of bone cancer pain. Sci Rep 2017; 7: 10949.
41. Dai Z, Chu H, Ma J, et al. The regulatory mechanisms and therapeutic potential of nicroRNAs: from chronic pain to morphine tolerance. Front Mol Neurosci 2018; 11: 80.
42. Hou XR, Weng Y, Guo Q, et al. Transcriptomic analysis of long noncoding RNAs and mRNAs expression profiles in the spinal cord of bone cancer pain rats. Mol Brain 2020; 13: 47.
43. Bali KK, Selvaraj D, Satagopam VP, et al. Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain. EMBO Mol Med 2013; 5: 1740-58.
44. Elramah S, López-González MJ, Bastide M, et al. Spinal miRNA-124 regulates synaptopodin and nociception in an animal model of bone cancer pain. Sci Rep 2017; 7: 10949.
45. Wang W, Xu X, Tian B, et al. The diagnostic value of serum tumor markers CEA, CA19- 9, CA125, CA15-3, and TPS in metastatic breast cancer. Clin Chim Acta 2017; 470: 51-5.
46. Deng GC, Yan H, Guo ZP, et al. Correlation between baseline serum tumor markers and clinical characteristic factors in patients with advanced pancreatic cancer. Onco Targets Ther 2020; 13: 11151-63.
47. Wang J, Chu Y, Li J, et al. Development of a prediction model with serum tumor markers to assess tumor metastasis in lung cancer. Cancer Med 2020; 9: 5436-45.
48. Shi WQ, Liu WF, Li B, et al. Assessment of serum tumor markers for predicting ocular metastasis in lung adenocarcinoma: a retrospective study. Dis Markers 2020; 2020: 2102158.
49. Backes C, Meese E, Keller A. Specific miRNA disease biomarkers in blood, serum and plasma: challenges and prospects. Mol Diagn Ther 2016; 20: 509-18.
50. Dong CS, Wu RX. Discussion on the pathogenesis of tumor "Zheng-Xu-Xie-Shi Syndrome" and its treatment based on metabolism. Zhejiang Zhong Yi Za Zhi 2023; 58: 175-6.
Outlines

/