Table Info

Table 3.

Selected effects of TCMs on PD-1/PD-L1 linkage

Class of TCM studied	ICB expression studied	Mode of study	Combination	Cancer	Year	Ref.
Qiyusanlong	PD-1/PD-L1	In vivo	Nil	Lung	2016	[73]
Ginsenoside Rg3	PD-L1	In vitro	ChT	Lung	2017	[74]
Baicalein	PD-L1	In vitro	Nil	HCC	2019	[75]
Gegen Qinlian	PD-1	In vitro	Nil	CRC	2019	[76]
Bu-zhong-yi-qi	PD-1/PD-L1	Clinical + in vitro	ChT	Gastric	2020	[77]
Ginsenoside Rk1	PD-L1	In vitro + in vivo	Nil	Lung	2020	[78]
Biochanin A	PD-L1	In vitro + in vivo	Nil	CRC	2022	[79]
Pien Tze Huang	PD-L1	In vitro + in vivo	Nil	CRC	2022	[80]

Recently, various classes of TCM preparations have increasingly been found to have suppression of ICB effects. Here, selected effects of TCM on PD-1/PD-L1 linkage are highlighted. Ref.: reference

Declarations

Author contributions

The author contributed solely to the work.

Conflicts of interest

The author declares no conflicts of interest in this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37:1470–8. [DOI] [PubMed]

Oaknin A, Gilbert L, Tinker AV, Brown J, Mathews C, Press J, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. J Immunother Cancer. 2022;10:e003777. [DOI] [PubMed] [PMC]

Mittica G, Ghisoni E, Giannone G, Aglietta M, Genta S, Valabrega G. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. Oncotarget. 2017;8:90532–44. [DOI] [PubMed] [PMC]

Noman MZ, Hasmim M, Lequeux A, Xiao M, Duhem C, Chouaib S, et al. Improving cancer immunotherapy by targeting the hypoxic tumor microenvironment: new opportunities and challenges. Cells. 2019;8:1083. [DOI] [PubMed] [PMC]

Gotink KJ, Verheul HMW. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13:1–14. [DOI] [PubMed] [PMC]

Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31:2205–18. [DOI] [PubMed] [PMC]

Horsman MR, Vaupel P. Pathophysiological basis for the formation of the tumor microenvironment. Front Oncol. 2016;6:66. [DOI] [PubMed] [PMC]

Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80:51–60. [PubMed] [PMC]

Vaupel P, Multhoff G. Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol. 2021;599:1745–57. [DOI] [PubMed]

10.

Tesi RJ. MDSC; the most important cell you have never heard of. Trends Pharmacol Sci. 2019;40:4–7. [DOI] [PubMed]

11.

Lee CC, Wu CY, Yang HY. Discoveries of how cells sense oxygen win the 2019 Nobel Prize in Physiology or medicine. Biomed J. 2020;43:434–7. [DOI] [PubMed] [PMC]

12.

Wang S, Cai R, Ma J, Liu T, Ke X, Lu H, et al. The natural compound codonolactone impairs tumor induced angiogenesis by downregulating BMP signaling in endothelial cells. Phytomedicine. 2015;22:1017–26. [DOI] [PubMed]

13.

Wu XY, Xu H, Wu ZF, Chen C, Liu JY, Wu GN, et al. Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models. Oncotarget. 2015;6:44563–78. [DOI] [PubMed] [PMC]

14.

Xie J, Liu J, Liu H, Liang S, Lin M, Gu Y, et al. The antitumor effect of tanshinone IIA on anti-proliferation and decreasing VEGF/VEGFR2 expression on the human non-small cell lung cancer A549 cell line. Acta Pharm Sin B. 2015;5:554–63. [DOI] [PubMed] [PMC]

15.

Cockman ME, Webb JD, Kramer HB, Kessler BM, Ratcliffe PJ. Proteomics-based identification of novel factor inhibiting hypoxia-inducible factor (FIH) substrates indicates widespread asparaginyl hydroxylation of ankyrin repeat domain-containing proteins. Mol Cell Proteomics. 2009;8:535–46. [DOI] [PubMed] [PMC]

16.

Aref AR, Campisi M, Ivanova E, Portell A, Larios D, Piel BP, et al. 3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Lab Chip. 2018;18:3129–43. [DOI] [PubMed] [PMC]

17.

Georganaki M, van Hooren L, Dimberg A. Vascular targeting to increase the efficiency of immune checkpoint blockade in cancer. Front Immunol. 2018;9:3081. [DOI] [PubMed] [PMC]

18.

Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8⁺ T cells in tumors. J Exp Med. 2015;212:139–48. [DOI] [PubMed] [PMC]

19.

Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26:605–22. [DOI] [PubMed] [PMC]

20.

Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325–40. [DOI] [PubMed] [PMC]

21.

Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018;15:310–24. [DOI] [PubMed]

22.

Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol. 2018;18:195–203. [DOI] [PubMed] [PMC]

23.

Wu JB, Tang YL, Liang XH. Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy. Onco Targets Ther. 2018;11:6901–9. [DOI] [PubMed] [PMC]

24.

Jha RM, Kochanek PM, Simard JM. Pathophysiology and treatment of cerebral edema in traumatic brain injury. Neuropharmacology. 2019;145:230–46. [DOI] [PubMed] [PMC]

25.

Akdemir H, Kontaş O, Oktem IS, Tucer B, Kafadar H, Paşaoğlu A. A new subtype of meningioma. Neurosurg Rev. 1999;22:50–3. [DOI] [PubMed]

26.

Nielsen SR, Schmid MC. Macrophages as key drivers of cancer progression and metastasis. Mediators Inflamm. 2017;2017:9624760. [DOI] [PubMed] [PMC]

27.

Eiro N, González L, Martïnez-Ordoñez A, Fernandez-Garcia B, González LO, Cid S, et al. Cancer-associated fibroblasts affect breast cancer cell gene expression, invasion and angiogenesis. Cell Oncol (Dordr). 2018;41:369–78. [DOI] [PubMed]

28.

Tsao SY. The role of metronomic chemotherapy in the era of cancer immunotherapy: an oncologist’s perspective. Curr Oncol. 2019;26:e422–4. [DOI] [PubMed] [PMC]

29.

Vacchelli E, Galluzzi L, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, et al. Trial watch: chemotherapy with immunogenic cell death inducers. Oncoimmunology. 2012;1:179–88. [DOI] [PubMed] [PMC]

30.

Shen G, Wang YJ, Guan YJ, Dong DP, Yang G, Li D, et al. Relief effect of bevacizumab on severe edema induced by re-irradiation in brain tumor patients. Chin Med J (Engl). 2015;128:2126–9. [DOI] [PubMed] [PMC]

31.

Meng X, Zhao R, Shen G, Dong D, Ding L, Wu S. Efficacy and safety of bevacizumab treatment for refractory brain edema: case report. Medicine (Baltimore). 2017;96:e8280. [DOI] [PubMed] [PMC]

32.

Bai X, Zhang Y, Ding W, Wang S. Efficacy of bevacizumab in the treatment of refractory brain edema of metastatic tumors from different sources. Neurol Res. 2021;43:955–60. [DOI] [PubMed]

33.

Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388:518–29. [DOI] [PubMed]

34.

Weinmann A, Galle PR. Role of immunotherapy in the management of hepatocellular carcinoma: current standards and future directions. Curr Oncol. 2020;27:S152–64. [DOI] [PubMed] [PMC]

35.

Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862–73. [DOI] [PubMed]

36.

Motzer RJ, Powles T, Burotto M, Escudier B, Bourlon MT, Shah AY, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:888–98. [DOI]

37.

McGregor B, Mortazavi A, Cordes L, Salabao C, Vandlik S, Apolo AB. Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: a review. Cancer Treat Rev. 2022;103:102333. [DOI] [PubMed]

38.

Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–9. [DOI] [PubMed] [PMC]

39.

Yoon Y, Kim G, Jeon BN, Fang S, Park H. Bifidobacterium strain-specific enhances the efficacy of cancer therapeutics in tumor-bearing mice. Cancers (Basel). 2021;13:957. [DOI] [PubMed] [PMC]

40.

Lee KA, Luong MK, Shaw H, Nathan P, Bataille V, Spector TD. The gut microbiome: what the oncologist ought to know. Br J Cancer. 2021;125:1197–209. [DOI] [PubMed] [PMC]

41.

van Beurden YH, Nieuwdorp M, van de Berg PJEJ, Mulder CJJ, Goorhuis A. Current challenges in the treatment of severe Clostridium difficile infection: early treatment potential of fecal microbiota transplantation. Therap Adv Gastroenterol. 2017;10:373–81. [DOI] [PubMed] [PMC]

42.

DeFilipp Z, Hohmann E, Jenq RR, Chen YB. Fecal microbiota transplantation: restoring the injured microbiome after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019;25:e17–22. [DOI] [PubMed]

43.

Gupta S, Parker J, Smits S, Underwood J, Dolwani S. Persistent viral shedding of SARS-CoV-2 in faeces – a rapid review. Colorectal Dis. 2020;22:611–20. [DOI] [PubMed] [PMC]

44.

Dailey FE, Turse EP, Daglilar E, Tahan V. The dirty aspects of fecal microbiota transplantation: a review of its adverse effects and complications. Curr Opin Pharmacol. 2019;49:29–33. [DOI] [PubMed]

45.

Shi Y, Fang J, Zhou C, Liu A, Wang Y, Meng Q, et al. Immune checkpoint inhibitor-related adverse events in lung cancer: real-world incidence and management practices of 1905 patients in China. Thorac Cancer. 2022;13:412–22. [DOI] [PubMed] [PMC]

46.

Tingry T, Massy E, Piperno M, Auroux M, Kostine M, Maillet D, et al. Rheumatic immune adverse events related to immune checkpoint inhibitors-(IrAEs related to ICI). Bull Cancer. 2021;108:643–53. French. [DOI] [PubMed]

47.

Zhang J, Zhou Y, Ma Z. Multi-target mechanism of Tripteryguim wilfordii Hook for treatment of ankylosing spondylitis based on network pharmacology and molecular docking. Ann Med. 2021;53:1090–8. [DOI] [PubMed] [PMC]

48.

Jiang H, Li J, Wang L, Wang S, Nie X, Chen Y, et al. Total glucosides of paeony: a review of its phytochemistry, role in autoimmune diseases, and mechanisms of action. J Ethnopharmacol. 2020;258:112913. [DOI] [PubMed]

49.

Wang YN, Zhang Y, Wang Y, Zhu DX, Xu LQ, Fang H, et al. The beneficial effect of total glucosides of paeony on psoriatic arthritis links to circulating Tregs and Th1 cell function. Phytother Res. 2014;28:372–81. [DOI] [PubMed]

50.

Wang S, Li R, He S, He L, Zhao H, Deng X, et al. Tripterygium wilfordii glycosides upregulate the new anti-inflammatory cytokine IL-37 through ERK1/2 and p38 MAPK signal pathways. Evid Based Complement Alternat Med. 2017;2017:9148523. [DOI] [PubMed] [PMC]

51.

Shi X, Zhu D, Nicholas S, Hong B, Man X, He P. Is traditional Chinese medicine “mainstream” in China? Trends in traditional Chinese medicine health resources and their utilization in traditional Chinese medicine hospitals from 2004 to 2016. Evid Based Complement Alternat Med. 2020;2020:9313491. [DOI] [PubMed] [PMC]

52.

Elekta assists China in reducing cost of oncotherapy [Internet]. Shanghai: China International Import Expo Bureau, Ministry of Commerce, China; c2017 [cited 2022 Jun 10]. Available from: https://www.ciie.org/zbh/ExhibitorDialogue/20181101/7588.html

53.

Aboushanab TS, AlSanad S. Cupping therapy: an overview from a modern medicine perspective. J Acupunct Meridian Stud. 2018;11:83–7. [DOI] [PubMed]

54.

Liu X, Xu F, Wang G, Diao X, Li Y. Kanglaite injection plus chemotherapy versus chemotherapy alone for non-small cell lung cancer patients: a systematic review and meta-analysis. Curr Ther Res Clin Exp. 2008;69:381–411. [DOI] [PubMed] [PMC]

55.

Ohmori T, Yamaoka T, Ando K, Kusumoto S, Kishino Y, Manabe R, et al. Molecular and clinical features of EGFR-TKI-associated lung injury. Int J Mol Sci. 2021;22:792. [DOI] [PubMed] [PMC]

56.

Ye L, Jia Y, Ji KE, Sanders AJ, Xue K, Ji J, et al. Traditional Chinese medicine in the prevention and treatment of cancer and cancer metastasis. Oncol Lett. 2015;10:1240–50. [DOI] [PubMed] [PMC]

57.

Duan GC. The effects of combination of coix seed extract and cisplatin on TAM and expression of HIF-1α in vivo in Lewis lung carcinoma. Iran J Public Health. 2018;47:838–43. [PubMed] [PMC]

58.

Xu D, Lin H, Tang Y, Huang L, Xu J, Nian S, et al. Integration of full-length transcriptomics and targeted metabolomics to identify benzylisoquinoline alkaloid biosynthetic genes in Corydalis yanhusuo. Hortic Res. 2021;8:16. [DOI] [PubMed] [PMC]

59.

Sheehan MP, Atherton DJ. A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema. Br J Dermatol. 1992;126:179–84. [DOI] [PubMed]

60.

Zhang E, Shi H, Yang L, Wu X, Wang Z. Ginsenoside Rd regulates the Akt/mTOR/p70S6K signaling cascade and suppresses angiogenesis and breast tumor growth. Oncol Rep. 2017;38:359–67. [DOI] [PubMed]

61.

Zhang Z, Li C, Tan Q, Xie C, Yang Y, Zhan W, et al. Curcumin suppresses tumor growth and angiogenesis in human glioma cells through modulation of vascular endothelial growth factor/angiopoietin-2/thrombospondin-1 signaling. CNS Neurol Disord Drug Targets. 2017;16:346–50. [DOI] [PubMed]

62.

Cathcart MC, Useckaite Z, Drakeford C, Semik V, Lysaght J, Gately K, et al. Anti-cancer effects of baicalein in non-small cell lung cancer in-vitro and in-vivo. BMC Cancer. 2016;16:707. [DOI] [PubMed] [PMC]

63.

Lin Y, Zhao WR, Shi WT, Zhang J, Zhang KY, Ding Q, et al. Pharmacological activity, pharmacokinetics, and toxicity of timosaponin AIII, a natural product isolated from Anemarrhena asphodeloides bunge: a review. Front Pharmacol. 2020;11:764. [DOI] [PubMed] [PMC]

64.

Lin J, Feng J, Jin Y, Yan Z, Lai Z, Peng J. Pien Tze Huang suppresses VEGF-C-mediated lymphangiogenesis in colorectal cancer. Oncol Rep. 2016;36:3568–76. [DOI] [PubMed]

65.

Liu T, Zhao L, Zhang Y, Chen W, Liu D, Hou H, et al. Ginsenoside 20(S)-Rg3 targets HIF-1α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells. PLoS One. 2014;9:e103887. [DOI] [PubMed] [PMC]

66.

Chen H, Shen A, Zhang Y, Chen Y, Lin J, Lin W, et al. Pien Tze Huang inhibits hypoxia-induced epithelial-mesenchymal transition in human colon carcinoma cells through suppression of the HIF-1 pathway. Exp Ther Med. 2014;7:1237–42. [DOI] [PubMed] [PMC]

67.

Wang H, Zhang C, Xu L, Zang K, Ning Z, Jiang F, et al. Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway. Oncotarget. 2016;7:20193–208. [DOI] [PubMed] [PMC]

68.

Hou F, Li W, Shi Q, Li H, Liu S, Zong S, et al. Yi Ai Fang, a traditional Chinese herbal formula, impacts the vasculogenic mimicry formation of human colorectal cancer through HIF-1α and epithelial mesenchymal transition. BMC Complement Altern Med. 2016;16:428. [DOI] [PubMed] [PMC]

69.

Qi F, Wei L, Shen A, Chen Y, Lin J, Chu J, et al. Pien Tze Huang inhibits the proliferation, and induces the apoptosis and differentiation of colorectal cancer stem cells via suppression of the Notch1 pathway. Oncol Rep. 2016;35:511–7. [DOI] [PubMed]

70.

Link A, Balaguer F, Shen Y, Lozano JJ, Leung HC, Boland CR, et al. Curcumin modulates DNA methylation in colorectal cancer cells. PLoS One. 2013;8:e57709. [DOI] [PubMed] [PMC]

71.

Hou YC, Wu JM, Wang MY, Wu MH, Chen KY, Yeh SL, et al. Modulatory effects of astragalus polysaccharides on T-cell polarization in mice with polymicrobial sepsis. Mediators Inflamm. 2015;2015:826319. [DOI] [PubMed] [PMC]

72.

Cui Y, Wang Q, Sun R, Guo L, Wang M, Jia J, et al. Astragalus membranaceus (Fisch.) Bunge repairs intestinal mucosal injury induced by LPS in mice. BMC Complement Altern Med. 2018;18:230. [DOI] [PubMed] [PMC]

73.

Zhang X, Tong J, Li Z. Qiyusanlong decoction inhibits the level of PD-1/PD-L1 in mice bearing Lewis lung carcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2016;32:770–4. Chinese. [PubMed]

74.

Jiang Z, Yang Y, Yang Y, Zhang Y, Yue Z, Pan Z, et al. Ginsenoside Rg3 attenuates cisplatin resistance in lung cancer by downregulating PD-L1 and resuming immune. Biomed Pharmacother. 2017;96:378–83. [DOI] [PubMed]

75.

Ke M, Zhang Z, Xu B, Zhao S, Ding Y, Wu X, et al. Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells. Int Immunopharmacol. 2019;75:105824. [DOI] [PubMed]

76.

Lv J, Jia Y, Li J, Kuai W, Li Y, Guo F, et al. Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment. Cell Death Dis. 2019;10:415. [DOI] [PubMed] [PMC]

77.

Xu R, Wu J, Zhang X, Zou X, Li C, Wang H, et al. Modified Bu-zhong-yi-qi decoction synergies with 5 fluorouracil to inhibits gastric cancer progress via PD-1/PD- L1-dependent T cell immunization. Pharmacol Res. 2020;152:104623. [DOI] [PubMed]

78.

Hu M, Yang J, Qu L, Deng X, Duan Z, Fu R, et al. Ginsenoside Rk1 induces apoptosis and downregulates the expression of PD-L1 by targeting the NF-κB pathway in lung adenocarcinoma. Food Funct. 2020;11:456–71. [DOI] [PubMed]

79.

Xu J, Yang X, Pan J, Fan H, Mei J, Hua D. Biochanin A suppresses tumor progression and PD-L1 expression via inhibiting ZEB1 expression in colorectal cancer. J Oncol. 2022;2022:3224373. [DOI] [PubMed] [PMC]

80.

Chen Q, Hong Y, Weng S, Guo P, Li B, Zhang Y, et al. Traditional Chinese medicine Pien-Tze-Huang inhibits colorectal cancer growth and immune evasion by reducing β-catenin transcriptional activity and PD-L1 expression. Front Pharmacol. 2022;13:828440. [DOI] [PubMed] [PMC]

81.

Wang J, Xia Y, Zuo Q, Chen T. Molecular mechanisms underlying the antimetastatic activity of bufalin. Mol Clin Oncol. 2018;8:631–6. [DOI] [PubMed] [PMC]

82.

Zhao HT, Meng YB, Zhai XF, Cheng BB, Yu SS, Yao M, et al. Comparable effects of Jiedu Granule, a compound Chinese herbal medicine, and sorafenib for advanced hepatocellular carcinoma: a prospective multicenter cohort study. J Integr Med. 2020;18:319–25. [DOI] [PubMed]

83.

Hassanipour S, Vali M, Gaffari-Fam S, Nikbakht HA, Abdzadeh E, Joukar F, et al. The survival rate of hepatocellular carcinoma in Asian countries: a systematic review and meta-analysis. EXCLI J. 2020;19:108–30. [DOI] [PubMed] [PMC]

84.

Liu J, Wang S, Zhang Y, Fan HT, Lin HS. Traditional Chinese medicine and cancer: history, present situation, and development. Thorac Cancer. 2015;6:561–9. [DOI] [PubMed] [PMC]

85.

Olweny CL, Toya T, Katongole-Mbidde E, Mugerwa J, Kyalwazi SK, Cohen H. Treatment of hepatocellular carcinoma with adriamycin. Preliminary communication. Cancer. 1975;36:1250–7. [DOI] [PubMed]

86.

Chen LY, Zhai XF, Chen Z, Zhu JF, Qian PA, Zhao HT, et al. Jie-du granule preparation for the treatment of advanced hepatocellular carcinoma: a retrospective cohort study of 177 patients. Oncotarget. 2017;8:30471–6. [DOI] [PubMed] [PMC]

87.

Shim JS, Kim JH, Lee J, Kim SN, Kwon HJ. Anti-angiogenic activity of a homoisoflavanone from Cremastra appendiculata. Planta Med. 2004;70:171–3. [DOI] [PubMed]

88.

Eleftheriadis T. What may constrain the success of indoleamine 2,3-dioxygenase 1 inhibitors in cancer immunotherapy? Front Immunol. 2018;9:1879. [DOI] [PubMed] [PMC]

89.

Chu H, Moon S, Park J, Bak S, Ko Y, Youn BY. The use of artificial intelligence in complementary and alternative medicine: a systematic scoping review. Front Pharmacol. 2022;13:826044. [DOI] [PubMed] [PMC]

90.

Song Y, Zhao B, Jia J, Wang X, Xu S, Li Z, et al. A review on different kinds of artificial intelligence solutions in TCM syndrome differentiation application. Evid Based Complement Alternat Med. 2021;2021:6654545. [DOI] [PubMed] [PMC]

91.

Blaszczak W, Swietach P. What do cellular responses to acidity tell us about cancer? Cancer Metastasis Rev. 2021;40:1159–76. [DOI] [PubMed] [PMC]

92.

Ulivi P, Marisi G, Passardi A. Relationship between hypoxia and response to antiangiogenic therapy in metastatic colorectal cancer. Oncotarget. 2016;7:46678–91. [DOI] [PubMed] [PMC]

93.

Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci U S A. 2009;106:17910–5. [DOI] [PubMed] [PMC]

94.

Seredinski S, Boos F, Günther S, Oo JA, Warwick T, Izquierdo Ponce J, et al. DNA topoisomerase inhibition with the HIF inhibitor acriflavine promotes transcription of lncRNAs in endothelial cells. Mol Ther Nucleic Acids. 2022;27:1023–35. [DOI] [PubMed] [PMC]

95.

Xu J, Song Z, Guo Q, Li J. Synergistic effect and molecular mechanisms of traditional Chinese medicine on regulating tumor microenvironment and cancer cells. Biomed Res Int. 2016;2016:1490738. [DOI] [PubMed] [PMC]

96.

Gong B, Kao Y, Zhang C, Zhao H, Sun F, Gong Z. Exploring the pharmacological mechanism of the herb pair “HuangLian-GanJiang” against colorectal cancer based on network pharmacology. Evid Based Complement Alternat Med. 2019;2019:2735050. [DOI] [PubMed] [PMC]

97.

Wang Y, Zhang Q, Chen Y, Liang CL, Liu H, Qiu F, et al. Antitumor effects of immunity-enhancing traditional Chinese medicine. Biomed Pharmacother. 2020;121:109570. [DOI] [PubMed]

98.

Shetty YC, Brahma S, Manjesh PS. Compassionate drug use: current status in India. Perspect Clin Res. 2020;11:3–7. [DOI] [PubMed] [PMC]

99.

Mir O, Alexandre J, Coriat R, Ropert S, Boudou-Rouquette P, Bui T, et al. Safety of bevacizumab 7.5 mg/kg infusion over 10 minutes in NSCLC patients. Invest New Drugs. 2012;30:1756–60. [DOI] [PubMed]

100.

Wu KK, Tsao SY. Tradition: the fiddler on the roof. In: Tsao SY, editor. Bridging the gap: in this era of cancer immunotherapy. New York: Nova Science; 2021. pp. 221–55.

101.

Xiao B, Wang W, Zhang D. Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials. Onco Targets Ther. 2018;11:5059–74. [DOI] [PubMed] [PMC]