Table 1 Alkaloids in the tumor microenvironment have distinct functions during tumorigenesis

CAFs

TGF-β、OPN、SDF-1、VEGFA、IL-6、CXCL12、CXCL2、CXCL5、CCL2

Conophylline decreased IL-6, IL-8, CCL2, and CXCL12 secreted by CAF to suppress CAF activity and proliferation. Agelastatin alkaloids inhibits transcription of OPN in mammary fibroblasts in TME which are associated with increased invasiveness in cancers

[30,31,32,33]

TILs

CD28,CD39,IFN-γ, PD-1、CD8⁺、CD4⁺、IL-2、IL-4、IL-5、IL-13、TGF-β、FOXP3

Homoharringtonine reduced IL-12 cytokine expression and enhanced B-cell 、T cell and NK cell activation. Caffeine reduces the immuno-suppressive within the tumor microenvironment of CLL by inhibiting PI3Kδ. Piperine suppress the TH1、Th2-mediated immune responses, including the STAT6/GATA3/IL-4 signaling pathway. Oxyatrine regulates DC-Treg system in TME by promoting the maturation of DC and mediate the differentiation of T cells into Treg cells

[47,48,49,50,51,52,53,54]

TAMs

M1 maker: iNOs、CD86、TNF-α、IL-12、IFN-γ

M2 maker: Arg-1、TGF-β1、CD206、IL-4、IL-10

Piperine exerts its anti-inflammatory effects via inhibition of COX-2 and NF-κB in murine macrophages. Curine treatment reduced cytokine levels and the expression of iNOS in vitro cultures of macrophages stimulated with LPS. Berberine inhibits the activation of NLRP3 inflammatory bodies to promote the polarization of M1. Ephedrine Hydrochloride increased IL-10 and decreased proinflammatory cytokine expression in primary peritoneal macrophages and Raw264.7 cells. Sophoridine can up-regulate the expression of iNOS, IFN-γ, IL-12α and down-regulate the expression of Arg-1, CD206 and IL-10, and have an effect on the polarization of TAMs in gastric TME. Solanine A suppressed LPS or INF-γ activated macrophages by inhibiting NF-κB, ERK1/2, AKT and STAT1 signaling pathways. Homoharringtonine inhibits STAT3 to suppress growth of cancer cells and sensitize cancer cells to the antitumor drugs. Lappaconitine inhibits the production of NO, PGE2 and TNF- α by inhibiting NF-kB and MAPK signaling pathways. Paclitaxel skews TAMs towards an immunocompetent profile via TLR4, which might contribute to the antitumor effect of PCX

[53, 70,71,72,73, 76,77,78,79,80,81,82, 84, 85, 88, 90]

MSCs/CSCs

VEGF, TRAIL

Ptx-PLGA NP-primed MSCs had enhanced sustained Ptx release in the form of free Ptx and Ptx NPs. Ptx transfer from MSCs to glioma cells could induce tumor cell death. Berberine reduce SDF-1 protein level secreted by BMSCs in the microenvironment to inhibit AML cells migration. LCL-HHT-H-PEG have an inhibitory effect on MM RPMI8226 CD138-CD34-CSCs. MASM inhibits hepatic cancer stem-like cells and markedly reduces the number of surviving cancer stem-like cells in the tumors. Isoharringtonine had inhibitory effects on BCSCs in breast cancer cell lines via inhibition of the STAT3/Nanong pathway.Berberis libanotica Ehrenb extract were sufficient to remove the self-renewal ability of highly resistant CSCs

[97, 99,100,101, 108, 109, 111, 112]

TAAs

IL-4, GFAP

Stachydrine suppresses proliferation and colony formation in Pilocytic astrocytoma cells through downregulated CXCR4 transcription and enhancing IκBα-based NF-κB inhibition. Palmatine suppresses glutamine-mediated changes in GLI signaling in PCCs while induces apoptosis by inhibition of survivin to disrupt reciprocal interaction between PSCs and PCCs in the TME

Conophylline reduced liver and pancreatic fibrosis by suppression of stellate cells

[30, 115, 119, 121]

Angiogenesis

VEGF

α-solanine treatment significantly reduce the expression of VEGF and endothelial cell tube formation

Berberine prevents the expression of HIF-1 to inhibit tumor-induced angiogenesis in hypoxic gastric cancer cells、HCC cells and human umbilical vein endothelial cells. Evodiaminevia down-regulation of VEGF expression and inhibition of tumor microangiogenesis in CRC mice modle. Narciclasine inhibits angiogenic processes through activation of Rho kinase and downregulation of the VEGF receptor 2

[124, 126, 128,129,130,131,132]

EMT

E-cadherin、N-cadherin、Vimentin、Twist

Piperine reversed the biomarker expression of EMT, and inhibits colorectal cancer migratory and invasive capacities through STAT3/ Snail mediated EMT. Sanguinarine inhibits the expression of EMT markers and also impairs HIF-1α and TGF-β form a feed-forward loop induce EMT in HCC cells. Sinomenine Hydrochloride suppressed the activation of NF-κB and the expression of MMP-2/-9, triggered ER stress, reversed the exogenous EMT. Berberine induced EMT changes in colonic epithelial cells with decreased E-cadherin and increased vimentin and α-SMA expression

Halofuginone inhibits phosphorylation of SMAD proteins in response to TGF-β. Neferine suppressed EMT through an upregulation of E-cadherin and downregulation of Vimentin, Snail and N-cadherin and TGF-β

[2, 8, 39, 134,135,136,137,138,139,140,141,142]

ECM

MMPs

Morphine reducts the circulating MMP-9 and u-PA through modulation of paracrine communication between cancer cells and non-malignant cells in the tumor microenvironment. Emetine regulates two major MAPKs, p38 and ERK.This leads to the selective down-regulation of MMP-2 and MMP-9

[3, 146, 147]

ROS

–

Koumine possesses the cytoprotective effects by suppressing production of ROS、caspase-3 activity and influencing the expression of Bax and Bcl-2. Capsaicin through ROS-JNK-CCAAT/enhancer binding protein homologous protein pathway to inhibit cell proliferation, metastasis and induce apoptosis. Sophoridine provoked the generation of ROS in pancreatic cancer cells to develop its anti-tumor effects. 5-pyrrolidine-coupled naphthyl dihydroisoquinoline alkaloid priority cytotoxicity to PANC-1 cells which proliferate rapidly in tumor microenvironment under hypoxia conditions to inhibiting the growth of tumor cell

[159,160,161,162]