Strategies for Remodeling the Tumor Microenvironment Using Active Ingredients of Ginseng—A Promising Approach for Cancer Therapy

Abstract

The tumor microenvironment (TME) plays a key role in promoting the initiation and progression of tumors, leading to chemoradiotherapy resistance and immunotherapy failure. Targeting of the TME is a novel anti-tumor therapeutic approach and is currently a focus of anti-tumor research. Panax ginseng C. A. Meyer (ginseng), an ingredient of well-known traditional Asia medicines, exerts beneficial anti-tumor effects and can regulate the TME. Here, we present a systematic review that describes the current status of research efforts to elucidate the functions and mechanisms of ginseng active components (including ginsenosides and ginseng polysaccharides) for achieving TME regulation. Ginsenosides have variety effects on TME, such as Rg3, Rd and Rk3 can inhibit tumor angiogenesis; Rg3, Rh2 and M4 can regulate the function of immune cells; Rg3, Rd and Rg5 can restrain the stemness of cancer stem cells. Ginseng polysaccharides (such as red ginseng acidic polysaccharides and polysaccharides extracted from ginseng berry and ginseng leaves) can regulate TME mainly by stimulating immune cells. In addition, we propose a potential mechanistic link between ginseng-associated restoration of gut microbiota and the tumor immune microenvironment. Finally, we describe recent advances for improving ginseng efficacy, including the development of a nano-drug delivery system. Taken together, this review provides novel perspectives on potential applications for ginseng active ingredients as anti-cancer adjuvants that achieve anti-cancer effects by reshaping the tumor microenvironment.

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

“…Interestingly, the optimized combination of Rg3 epimers (50 μM S -Rg3 + 25 μM R -Rg3) more effectively suppressed tube formation, migration, and proliferation of HUVECs than S -Rg3 and R -Rg3, respectively ( Nakhjavani et al, 2021 ). Although several ginsenosides active components of ginseng, including Rb1, Rg3, and Rd served as tumor angiogenesis inhibitors ( Li et al, 2021b ), it is noteworthy that the angiogenic modulation of the rest of the ginsenosides, containing protopanaxadiols, protopanaxatriols, and oleanane types ( Zhou et al, 2022 ), were incompletely investigated. In addition, neem leaf glycoprotein (NLGP), a natural immune-modulator obtained from the leaves of neem ( Azadirachta indica A. juss), balked M2 polarization of TAMs and HIF1α/VEGF signaling with STAT3-dependent manner and induced tumor vessel normalization with CD8 + T cells dependence by downmodulating VEGF and VEGFR2 ( Banerjee et al, 2014 ; Goswami et al, 2014 ; Saha et al, 2020 ).…”

“…What we are persuasively interested in is the local or ethnic medicine—derived molecules with properties of both anti-angiogenesis and TME remodeling, all of them provide a unique sight on the combined therapy of tumor angiogenesis inhibition and immune modulation. On the other hand, there are abundant evidences implying that natural products and their analogs have a crucial part in regulating TME, such as ginseng and silibinin ( Deep and Agarwal, 2013 ; Li et al, 2021b ), while in independent studies the anti-angiogenic attributes in some of them are also reported. The biologically active ingredients with TME regulatory and anti-angiogenic activities confirmed in independent and respective studies are considered second-line or potential evidences.…”

Research progress of ginseng in the treatment of gastrointestinal cancers

“…Li et al observed that GFP1 could inhibit tumor growth and lung metastasis in vivo by activating immune function, increasing the relative weights of the spleen and thymus, promoting splenic lymphocyte proliferation, and increasing splenic NK cell activity ( Lee et al, 2019 ). Li et al observed that GPS modulates the TME by stimulating immune cells ( Li et al, 2021b ). Li et al observed that polysaccharides prolonged the survival of HCC H22-bearing mice and that the use of GPS enhanced the host defense response against tumors ( Li et al, 2016b ).…”

“…In pancreatic cancer metastasis, 20(S)-GRh2 effectively inhibited IL-6-induced signaling and STAT3 phosphorylation, MMP-1, -2, and -9 expression, suppressed migration and invasion of pancreatic cancer Bxpc3 cells ( Li et al, 2021a ), prevented degradation of the extracellular matrix and basement membrane, and inhibited EMT progression ( Han et al, 2016 ). GRh2 also inhibited human pancreatic cancer cell Bxpc-3 migration by downregulating MMP-2 and MMP-9 ( Li et al, 2021b ).…”

“…Radiotherapy is also one of the basic tools of oncology treatment; however, tumor radiation resistance remains a major treatment obstacle. GRg3 enhances the radiosensitivity of esophageal ( Li et al, 2021b ) and colorectal cancers ( Liu T et al, 2018 ) by downregulating the VEGF, thereby reducing tumor size, inhibiting tumor growth, and prolonging survival. Nrf2, a key transcription factor that regulates resistance to oxidative stress, plays an important role in the induction of antioxidant responses in the body.…”