Extreme low dose of 5-fluorouracil reverses MDR in cancer by sensitizing cancer associated fibroblasts and down-regulating P-gp

Abstract

We conducted a prospective, meaningful study of extreme low dose of 5-fluorouracil (5FU) as a metronomic agent targeting cancer associated fibroblasts (CAFs) to reverse Multidrug resistance (MDR) by sensitizing cancer associated fibroblasts and down-regulating P-glycoprotein (P-gp). The combination of 5FU and Taxol inhibited resistant KB-8-5 tumor growth by 79% and H460/Tax-R tumor growth by 55%. The inhibition was significant for both tumor types compared with Taxol treatment alone (p<0.001 and p = 0.0067, respectively). Nevertheless, the low-dose 5FU (2.2 mg/kg compared to the therapeutic dose of 50–150 mg/kg) showed negligible tumor inhibitory effect. The tumor growth inhibition study on resistant tumors demonstrated that the continuous administration of low dose 5FU with Taxol significantly inhibited the tumor growth. The treatment overcomes drug resistance in tumors by down-regulating multi-drug resistance transporter protein (P-gp), and more importantly, by eliminating CAFs recruited by resistant tumors. Compared with traditional metronomic chemotherapy, 5FU as metronomic agent targeting CAFs can avoid the disadvantages resulted from the concomitant administration of antiangiogenetic drug. The approach has good translational potential for clinical trials when treating stroma-rich drug resistant tumors.

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

“…In addition, elevated expression and activity of P-gp have been reported to be associated with poor clinical outcomes among cancer patients [24]. Based on these findings, a rationale was formulated for modulation of P-gp activity as a therapeutic approach [25]. A large number of compounds including verapamil, cyclosporine A, curcuminoids, and curcumin was demonstrated to exert reversal effects on MDR.…”

circBIRC6 regulates cisplatin resistance of choroidal melanoma via positively modulating ERK by sponging miR-503-3p

“…The occurrence of cancer resistance is related to the abnormality of multiple genes and their products, including multidrug resistance gene 1 (MDR1), lung resistance-related protein (LRP), etc [36]. P-gp is an MDR1 gene expression product and is an ATP-dependent transporter that can transport intracellular chemotherapeutic drugs out of the cell, thereby reducing the e cacy of the drug and leading to the emergence of drug resistance [37]. This study found that pCDS-circBIRC6 inhibited P-gp and MRP1 protein expression, and si-circBIRC6 increased the resistance to adverse reactions of DDP.…”

Tumor-Associated Fibroblast-Targeting Nanoparticles for Enhancing Solid Tumor Therapy: Progress and Challenges

“…This is due to the fact that at a very low dose, 5 can target TAFs and inhibit multidrug resistance protein (Pgp). 52 In addition to the direct use of chemodrugs, nanotechnology-based drugs can also inhibit TAFs and thus improve antitumor efficacy. For example, to promote the penetration of nanomedicines into tumors and block stromal support to cancer cells, novel tumor stromal-targeted nanoparticles (FH-SSL-NAV) were designed to eliminate TAFs.…”

“…Studies have indicated that combination of paclitaxel with a low dose of 5-FU can effectively inhibit tumor growth hormone, and improve the effectiveness of chemotherapy. This is due to the fact that at a very low dose, 5-FU can target TAFs and inhibit multidrug resistance protein (P-gp) …”