Currently, malignant tumors are a serious threat to human health and life, and are one of the major causes of human death, with their incidence increasing year by year. The treatment of tumors is clinically based on surgery or radiotherapy, supplemented by bioimmunotherapy and Chinese medicine. Chemotherapy is an important treatment for most tumor patients. A small number of tumors can be cured clinically by chemotherapy, however, for most tumors chemotherapy drugs cannot eradicate the tumor fundamentally. One of the main reasons for chemotherapy failure is tumor drug resistance. Tumor drug resistance can be divided into primary drug resistance and acquired drug resistance, which refer to the resistance that tumor cells already have when they are not exposed to chemotherapy drugs and the resistance that develops gradually during the chemotherapy process, respectively. While tumor cells are resistant to one antitumor drug, they are often cross-resistant to antitumor drugs with completely different structures and mechanisms of action, a phenomenon that has become multidrug resistance (MDR) in tumors and is a key cause of radiotherapy failure and tumor recurrence. 1. P-gp human P-gp is a phosphorylated and glycosylated It is encoded by the ABCB1 (MDRI) gene, located on human chromosome 7q21.1, and consists of 1280 amino acids with a molecular weight of 170,000, containing two homologous monomers, each containing six hydrophobic transmembrane parts and one intracellular ATP binding site, and the highly conserved “Walker A” and “Walker B” monomers. “and “Walker B” structures. A variety of chemotherapeutic drugs, including anthracyclines, vincristine, paclitaxel, onychomycin, mitoxantrone, mitomycin, etc. are its substrates. High expression of P-gp on tumor cells can reduce the accumulation of antitumor drugs in cells, which leads to the development of clinical drug resistance. Studies have confirmed the expression of the MDR1 gene in almost all types of tumors, including sarcomas, leukemias, and lymphomas. Based on the level of MDR1 gene expression in human tumors, Nooter [6] classified tumors into three categories: (1) tumors with high MDR1 gene expression, such as kidney cancer, pancreatic cancer, and hepatocellular carcinoma. These tumors have moderate or high expression of the MDR1 gene in the tissue of origin itself and mostly show primary drug resistance and poor chemotherapy effects; (2) tumors with moderate expression of the MDR1 gene, such as breast cancer, neuroblastoma, and leukemia. These tumors are more sensitive, but most patients have recurrence after the end of chemotherapy. After recurrence, the level of MDR1 gene expression is higher, and they are resistant to the original sensitive chemotherapy drugs; (3) tumors with low MDR1 gene expression, such as ovarian cancer, small cell lung cancer, etc. Although these tumors are sensitive to chemotherapeutic agents, they can also develop multidrug resistance. burger et al [7] analyzed 59 primary breast cancer specimens by real-time quantitative RT-PCR and showed that the expression level of P-gp was negatively correlated with the initial treatment effect of chemotherapeutic agents, and tumors with high P-gp expression tended to have a poorer prognosis. p-gp has emerged as an important tumor target. P-gp inhibitors (MDR reversal agents, tumor chemotherapy sensitizers) [8] have recently become a hot topic of research, and they are divided into three generations according to the order of appearance and action characteristics of P-gp inhibitors: the first generation The research of inhibitors started in 1981. It was found that the calcium channel blocker verapamil could increase the concentration of chemotherapeutic drugs in tumor cells by directly competing with some antitumor drugs for the efflux of P-gp drug pumps, thus achieving the reversal of MDR. Other calcium channel blockers were later found to have similar effects. The first generation P-gp inhibitors also include: calmodulin antagonists, cyclosporine, quinolines and steroid hormones, among which cyclosporine has the strongest effect. Their main feature is that they can reverse or even completely reverse MDR in in vitro trials. but in vivo trials, due to their own dose-limiting toxicity, the concentrations needed to effectively reverse MDR cannot be achieved in vivo, such as the severe cardiovascular side effects seen with in vivo use of verapamil and the strong immunosuppressive toxicity of cyclosporine. The 1st generation reversal agents have serious side effects in humans before reaching low concentrations of the inhibited transporter proteins, thus losing their clinical application. The second-generation inhibitors were selected by modifying the structure of the first-generation inhibitors, and the compounds with high reversal activity and low toxic side effects are represented by PSC833 and VX-710 (analogs of cyclosporin D) and dexverapamil, dexniguldipine, etc. Since many chemotherapeutic drugs are substrates of both P – gp and cytochrome P450 isoenzyme 3A4, the competitive binding of sensitizers to P450 3A4 affects the metabolism of chemotherapeutic drugs, leading to an increase in the blood concentration of chemotherapeutic drugs and toxic side effects. For example, PSC833 is 10-20 times more potent than cyclophilin reversal, and when combined with antitumor drugs in animal models, it results in significant reduction in tumor size and effectively extends the life span of tumor-bearing animals [9]. However, in clinical trials, PSC833 was found to be able to produce toxic side effects by inhibiting cytochrome oxidase P450-3A4-mediated metabolism of paclitaxel and vincristine, resulting in a significant increase in plasma levels of cytotoxic drugs in patients [10].VX-710 is a reversal agent capable of inhibiting both P-gp and MRP activity [11], with a high reversal activity that is approximately more than 100-fold. However, VX-710 can significantly reduce the clearance of paclitaxel in tumor patients when combined with paclitaxel, leading to toxic side effects. The third generation P-gp inhibitors are characterized by overcoming the shortcomings of the second generation and do not affect their pharmacokinetics when combined with antitumor drugs. The main ones include GF120918, LY335979, Lanquidar (R101933), ONT2093 (OC1442093), and XR9576. The representative compounds that have entered clinical trials are LY335979 and XR9576. XR9576 is a new derivative of o-aminobenzoic acid, which is a highly specific inhibitor of P-gp, but it is not a substrate of P-gp and has no effect on MRP and BCRP. It is also one of the strongest P-gp reversal agents found so far. In vivo experiments have shown that XR9576 significantly enhances the therapeutic effects of adriamycin, vincristine and paclitaxel in human MDR tumor models, without affecting the drug metabolism of these drugs. Phase II clinical trials also confirmed its good reversal effect on some multidrug-resistant tumors [12]. Tests have shown that LY335979 can significantly reduce the tumor volume of tumor-bearing mice and improve the survival rate of experimental animals, and more importantly, LY335979 does not affect the metabolic kinetics of cytotoxic drugs, which has some prospects for development and application [13].2 The MRPMRP subfamily has nine main members: MRP1 to MRP7, ABCC11 and ABCC12, with basic structures Similar to P-gp, one of them consists of an N-terminal region with five α-helices, while MRP4 and MRP5 do not have this structure. All MRP glycosylation sites are on the outer part of the first transmembrane domain in part 2 and on the terminal extension structure.Colo et al. 1992 cloned the drug resistance-associated gene MRP from a small cell lung cancer H69 /AR drug-resistant cell line belonging to the MRPC family. Unlike P- gp, MRP mainly transports hydrophobic uncharged molecules or water-soluble anionic compounds. Many drugs that have been shown to reverse P- gp-mediated resistance are ineffective against MDR mediated by MRP. In hepatocellular carcinoma cells [14], MRP1 expression levels were found to correlate with tumor differentiation, type, and microvascular invasion, and significant upregulation of MRP1 was associated with a significantly worse prognosis for hepatocellular carcinoma. In a study of 162 patients with surgically resected hepatocellular carcinoma, it was found that high expression of MRP1-1666GG genotype was associated with low survival rate in hepatocellular carcinoma patients [15].VOREM et al [16] transfected a hepatocellular carcinoma cell line with HepG2 antisense cMOAT cDNA to suppress MRP2 gene transcription and found that the concentration of NA in transfected human cells was inversely correlated with MRP2 activity. The half-inhibitory concentrations of some corresponding chemotherapeutic drugs were also decreased in the cMOAT cDNA group. It was demonstrated that the transcriptional inhibition of MRP2 gene could enhance the chemosensitivity of hepatocellular carcinoma cells and reverse their multidrug resistance; currently, the following drugs were found to have the potential to reverse MRP-mediated MDR, including verapamil and its derivatives, cyclosporine A, flavonoids, antihormones, quinolines, GST enzyme inhibitors, NSAIDs such as aspirin, indomethacin, isozole; azoline derivatives, digoxin, etc. Verapamil can achieve reversal of MRP multidrug resistance by competitively binding to membrane resistance proteins (P- gp, MRP1) and increase the sensitivity of chemotherapeutic drugs by inhibiting the expression of resistance genes (P- gp, MRP1) [17]; Connor et al. in their study of NC IH460 cells overexpressing MRP1, also found that su-lindac (su-lindac) had the ability to reverse MRP1-mediated resistance to ADR [18 ]. The above drugs were able to enter the cells to inhibit MRP, but these inhibitors have low affinity and lack of specificity with MRP, probably because MRP mainly transports anionic compounds, and anionic compounds such as PAK -104P, NSAIDs and ONO1078 rarely enter the cells, so it is difficult for the inhibitors to reach effective inhibitory concentrations in the cells.3 BCRPBCRP is BCRP is a recently discovered ABC drug efflux transporter protein, which is a phosphorylated protein with a molecular weight of 95,000. Compared with other ABC transporter proteins, it is structurally a hemi-transporter protein with only six α-helices and one ATP binding site, and functions mostly as a homodimer in the cell membrane. It is believed that BCRP is localized in the cell membrane, which suggests that it may be mainly involved in intra- and extra-membrane drug transport, rather than altering the intracellular distribution of drugs. Rabindran [19] and others found that FTC can reduce drug resistance in tumor cells, increase intracellular drug aggregation, and effectively reverse mitoxantrone, adriamycin, and topotecan resistance. Moreover, it has a small effect on P -gp or MRP1-mediated resistance and has become a useful tool for pharmacological studies of BCRP, but cannot be used in animals and humans because of neurotoxicity. Various low toxicity and active FTC analogues such as Ko143 have been synthesized and are expected to become clinically useful[ 20] .Yasuo Imai et al. suggested that phytoestrogens ( phytoestro2gens) can reverse BCBP-mediated MDR, and it was found that phytoestrogens/flavonoids enhance the effect of SN – 38 and mitoxantrone on BCRP transduced K562 cells. Glycosylated flavonoids had no effect on both P – gp-mediated vincristine resistance and MRP1-mediated resistance to VP – 16, however both could increase the accumulation of topotecan in K562 /BCRP cells [ 21 ]. Researchers suggest that flavonoids and glycosylated flavonoids may become effective agents to overcome multidrug resistance mediated by BCRP in tumor cells, and if flavonoids are combined with antitumor drugs with BCRP substrates, they may alter the pharmacokinetics, thus increasing the cytotoxicity of specific antitumor drugs on tumor cells.Ahmed – Belkacem et al [ 22 ] in found that 6 – Prenylchrysin and Tectochrysin are specific inhibitors of BCRP. In comparison with GF120918, these two compounds had no effect on both P- gp and MRP, exhibited lower intracellular toxicity, and did not alter ATPase activity.Nakamura et al [ 23 ] found that Gefitinib could directly reverse BCRP-mediated MDR.In their study, 10 μmol Gefitinib was found to reverse the tumor cell response to topotecan Gefitinib directly inhibited topotecan transport to vesicles. Dipyridamole [ 24 ] was found to be a new substrate for BCRP, while some calcium blockers such as nicardipine, nifedipine and nimodipine effectively inhibited mitoxantrone efflux in BCRP overexpressing HEK ( human embryo kidney) cells, while fellow calcium blockers diltiazem and verapamil had no such effect. In recent years, research on the reversal of tumor drug resistance in Chinese medicine has also been widely conducted. Many studies have been conducted on the effects of active ingredients of herbal medicines on drug metabolizing enzymes and transporters, and some of these plant polyphenols, flavonoids, and terpenoids have been found to have some inhibitory effects on P-gp [25-27]. It has been demonstrated that Schisandra chinensis alcohol methyl A can enhance the cytotoxic effect of VCR on drug-resistant hepatocellular carcinoma cells HepG2/ADR by reversing P-gp-mediated multidrug resistance by affecting the formation and function of P-gp substrate complexes [28]. C. alba extracts also have a strong inhibitory effect on the growth of multidrug-resistant leukemia cells HL260/ADR, and the induction of apoptosis in MDR is the main mechanism [29]. In a K562/ADM nude mouse transplantation tumor model of multidrug resistance, Yaoqinghua Zhang et al [30] found that the compound Vineleaf root preparation could increase the concentration of ADM accumulation in tumor cells and achieve partial reversal of multidrug resistance in transplantation tumors, one of the mechanisms of which was achieved by inhibiting the increase of P-gp. Studies of Chinese medicine compound formulas are also being conducted simultaneously, and one study found that a formula consisting of Astragalus, Atractylodes, and Radix et Rhizoma North is able to significantly increase the proliferation inhibitory effect of cisplatin on drug-resistant cell line A549/DDP with a synergistic effect, and reversal of apoptotic resistance in A549/DDP cells may be one of its mechanisms of action in reversing MDR [31]. Chinese medicines often have anti-tumor and immune modulating functions while reversing tumor resistance, which is beneficial to improve the overall tumor treatment, and this is a new research area with promising clinical applications. It brings new hope for the development of clinical antitumor drugs and the discovery of new methods of antitumor therapy.