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The emergence of multidrug resistance (MDR) in malignant tumors is the primary reason for invalid chemotherapy. Antitumor drugs are often adversely affected by the MDR of tumor cells. Treatments using conventional drugs, which have specific drug targets, hardly regulate the complex signaling pathway of MDR cells because of the complex formation mechanism of MDR. However, natural products have positive advantages, such as high efficiency, low toxicity, and ability to target multiple mechanism pathways associated with MDR. Natural products, as MDR reversal agents, synergize with chemotherapeutics and enhance the sensitivity of tumor cells to chemotherapeutics, and the co-delivery of natural products and antitumor drugs with nanocarriers maximizes the synergistic effects against MDR in tumor cells. This review summarizes the molecular mechanisms of MDR, the advantages of natural products combined with chemotherapeutics in offsetting complicated MDR mechanisms, and the types and mechanisms of natural products that are potential MDR reversal modulators. Meanwhile, aiming at the low bioavailability of cocktail combined natural products and chemotherapeutic in vivo, the advantages of nanoplatform-based co-delivery system and recent research developments are illustrated on the basis of our previous research. Finally, prospective horizons are analyzed, which are expected to considerably improve the nano-co-delivery of natural products and chemotherapeutic systems for MDR reversal in cancer., (Copyright © 2021. Published by Elsevier B.V.)

Multidrug resistance (MDR) plays a pivotal role in human chronic myelogenous leukemia (CML) chemotherapy failure. MDR is mainly associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) proteins. Phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) expression in many human malignancies. Homeobox (HOX) B4, a member of the HOX gene family, has been reported to be correlated with occurrence, development, poor prognosis and drug resistance of human leukemia. In the present study, HOXB4 expression was analyzed in K562 cell line and its MDR subline K562/ADM. Compared with K562 cells, drug-resistant K562/ADM cells demonstrated evidently higher HOXB4 expression. In addition, we firstly investigated the reversal effect of HOXB4 deletion on K562/ADM cells and the underlying mechanism. The Cell Counting kit-8 (CCK-8) and flow cytometry assays showed that knockdown of HOXB4 enhanced chemosensitivity and decreased drug efflux in K562/ADM cells. Moreover, HOXB4 knockout led to downregulation of P-gp, MRP1 and BCRP expression and PI3K/Akt signaling activity, suggesting that repression of HOXB4 might be a key point to reverse MDR of K562/ADM cells.

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) has been reported to play a pivotal role in tumor chemotherapy failure. Study after study has illustrated that the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with P-gp expression in many human malignancies. In the present study, osthole, an O-methylated coumarin, exhibited potent reversal capability of MDR in myelogenous leukemia K562/ADM cells. Simultaneously, the uptake and efflux of Rhodamine-123 (Rh-123) and the accumulation of doxorubicin assays combined with flow cytometric analysis suggested that osthole could increase intracellular drug accumulation. Furthermore, osthole decreased the expression of multidrug resistance gene 1 (MDR1) at both the mRNA and protein levels. Further experiments elucidated that osthole could suppress P-gp expression by inhibiting the PI3K/Akt signaling pathway which might be the main mechanism accounting for the reversal potential of osthole in the MDR in K562/ADM cells. In conclusion, osthole combats MDR and could be a promising candidate for the development of novel MDR reversal modulators.

One of the major causes of failure in chemotherapy for patients with human chronic myelogenous leukemia (CML) is the acquisition of multidrug resistance (MDR). MDR is often associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. Timosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, has previously demonstrated the ability to suppress certain human tumor processes and the potential to be developed as an anticancer agent. Nevertheless, the ability of TAIII to reverse MDR has not yet been explored. In this study, the adriamycin (ADM) resistance reversal effect of TAIII in human CML K562/ADM cells and the underlying mechanism was investigated. The Cell Counting Kit-8 (CCK-8) assay showed that TAIII had a reversal effect on the drug resistance of K562/ADM cells. Flow cytometry assay showed increased intracellular accumulation of ADM after cells were pretreated with TAIII, and the changes in the accumulation of rhodamine-123 (Rho-123) and 5(6)-carboxyfluorescein diacetate (CFDA) dye in K562/ADM cells were determined to be similar to the changes of intracellular accumulation of ADM. After pretreatment of cells with TAIII, the decreasing expression of P-gp and MRP1 mRNA was examined by reverse transcription polymerase chain reaction (RT-PCR). Western blotting showed TAIII inhibiting P-gp and MRP1 expression depended on the PI3K/Akt signaling pathway by decreasing the activity of p-Akt. Moreover, wortmannin an inhibitor of PI3K/Akt signaling pathway has a strong inhibitory effect on the expression of p-Akt, P-gp and MRP1. Besides, the combined treatment with TAIII did not have an affect on wortmannin downregulation of p-Akt, P-gp and MRP1. Taken together, our findings demonstrate, for the first time, that TAIII induced MDR reversal through inhibition of P-gp and MRP1 expression and function with regained adriamycin sensitivity which might mainly correlate to the regulation of PI3K/Akt signaling pathway.

microRNAs (miRNAs) have been shown to play a role in cancer. Antisense oligonucleotides can bind directly to miRNAs and block their activity, which are generally named anti-miRNAs. To suppress A549 cell proliferation in vitro and in vivo by anti-miRNAs, an anti-miR-150 expression vector (PR-ASO-150), regulated by the H1 promoter and containing a 'TTTTT' sequence following a hairpin to stop transcription, was constructed. A549 cell proliferation in vitro or in nude mice was observed after PR-ASO-150 treatment. Our results showed that miR-150 expression was inhibited and the growth inhibition rate of A549 cells was higher in the PR-ASO-150-treated group compared with the control, which indicated that PR-ASO-150 could inhibit A549 cell proliferation by regulating miR-150 expression. Following establishment of A549 cancer cell xenografts in nude mice, PR-ASO-150 was delivered intratumorally to investigate the suppressive action to tumor proliferation by regulating miR-150 expression. The results indicate that the tumor volume and weight were lower compared to the control group. Our results further showed that p53 expression was higher after tumor tissue was treated with PR-ASO-150, indicating that up-regulation of p53 contributed to the suppression to tumor growth. Our study provides a novel strategy for cancer therapy through the development of anti-miRNAs.

To explore the mechanism of apoptosis induced by cisplatin, the expression of microRNAs (miRNAs) and regulating genes in K562 cells was analyzed using reverse transcription PCR, quantitative real-time PCR and enzyme-linked immunosorbent assays. Our results showed that miR-16, miR-34a-c, miR-17-5p and miR-125 were up-regulated, and their associated oncogenes (BCL2, E2F1 and E2F3, respectively) were down-regulated after cisplatin treatment. We also showed that miR-106 and miR-150 were down-regulated while their target genes (RB1 and P53, respectively) were up-regulated after cisplatin treatment. Moreover, miR-16, miR-34a-c and miR-17-5p proved to be upstream factors, regulating the expression of BCL2, E2F1 and E2F3, respectively. The oncogene E2F3 was down-regulated when RB1 expression was increased after treatment with antisense oligonucleotides (ASO). Similarly, BCL2 and E2F3 were down-regulated when P53 expression was elevated by ASO treatment. The study demonstrated that cisplatin induces K562 cells to apoptosis by reducing miR-106 which up-regulates RB1 or by inhibiting miR-150 which increases P53 expression.