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. 2020 Feb 15;12(2):551-562.
eCollection 2020.

Y-320, a Novel Immune-Modulator, Sensitizes Multidrug-Resistant Tumors to Chemotherapy

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Free PMC article

Y-320, a Novel Immune-Modulator, Sensitizes Multidrug-Resistant Tumors to Chemotherapy

Jiawei Hong et al. Am J Transl Res. .
Free PMC article

Abstract

Y-320, a novel immune-modulator, inhibits IL-17 production by CD4+ T cells stimulated with IL-15. Its use in autoimmune diseases such as rheumatoid arthritis has been documented. However, no studies have be conducted to evaluate its application in cancer treatment either as mono or combined therapy. This study demonstrated that while Y-320 had little effect on multidrug resistance (MDR) cell lines, it induced remarkable injury to MDR tumor cells when concurrently administered with other chemotherapeutic agents. Concomitant use of Y-320 with a low dose of paclitaxel significantly sensitized MDR tumors by inducing G2/M phase arrest and apoptosis. Further analyses indicated that Y-320 was a substrate of P-glycoprotein (P-gp). It could inhibit P-gp efflux function without altering P-gp expression, and subsequently reverse P-gp mediated drug resistance in MDR cells. The co-administration of Y-320 and paclitaxel suppressed tumor growth remarkably with an inhibition rate of 77.1% compared to 6.5% in the paclitaxel monotherapy group in vivo. This co-treatment did not increase extra complications in MDR tumor xenograft models. Particularly, no significant changes in body weight and hepatorenal serology were observed with the co-treatment. In conclusion, our results confirm that Y-320 is a promising chemotherapy sensitizer for the first time. The co-administration of Y-320 and chemotherapeutic agents might be an effective and low-toxicity chemotherapeutic regime for the MDR tumor patients.

Keywords: P-glycoprotein; Y-320; chemotherapy sensitizer; combined therapy; multidrug resistance.

Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Y-320 reverses the resistance to paclitaxel in various MDR cancer cells. A. The structural formula of Y-320. B. Bads-200, Bats-72 and Huh7-TS-48 were incubated with increasing doses of Y-320 alone for 72 h. C-H. Bads-200, Bats-72 and Huh7-TS-48 were exposed to a series of concentrations of paclitaxel with or without 500 nM Y-320 for 72 h. The IC50 of paclitaxel was determined with or without 500 nM Y-320 after 72 h treatment. The reversal index of Y-320 combined with paclitaxel was also calculated compared with paclitaxel group. I. Colony formation of Bads-200 with various treatments. Data are shown as mean ± SD. Student’s t-test was used for two-group comparisons. *P<0.05; **P<0.01; CTL, control; Y-320, 500 nM Y-320; PTX, 500 nM paclitaxel; PTX+Y-320, combination of 500 nM paclitaxel and 500 nM Y-320; RI, reversal index.
Figure 2
Figure 2
Y-320 enhances paclitaxel-induced G2/M block of tumor cell cycle. A. Morphological images of Bads-200 taken with an inverted microscope (×100) after different treatments for 72 h. B, C. Cell cycle analysis of Bads-200 after different treatments for 72 h and the G2/M phase histogram. D. Western blot analysis of cell cycle-related proteins, CDK1, Cyclin B1, CDK6 and PKM2 in Bads-200. Data are shown as mean ± SD. Student’s t-test was used for two-group comparisons. *P<0.05; **P<0.01; CTL, control; Y-320, 500 nM Y-320; PTX, 500 nM paclitaxel; PTX+Y-320, combination of 500 nM paclitaxel and 500 nM Y-320.
Figure 3
Figure 3
Y-320 enhances paclitaxel-induced tumor cell apoptosis. A, B. Apoptosis assay of Bads-200 after different treatments for 72 h. C. Western blot analysis of apoptosis-related proteins, PARP, C-PARP, Caspase3 and C-Caspase3 in Bads-200. Data are shown as mean ± SD. Student’s t-test was used for two-group comparisons. *P<0.05; **P<0.01; CTL, control; Y-320, 500 nM Y-320; PTX, 500 nM paclitaxel; PTX+Y-320, combination of 500 nM paclitaxel and 500 nM Y-320.
Figure 4
Figure 4
Y-320’s mechanism for sensitizing cancer cells to chemotherapeutic agents. A. Western blot analysis of P-gp proteins in Bads-200, Bats-72, BCap-37 and Huh7-TS-48. B. Western blot analysis of P-gp proteins in Bads-200 after differential treatment for 72 h. C, D. Intracellular Rh123 fluorescence intensity in Bads-200 with different treatments. E. The effect of Y-320 on the ATPase activity of P-gp compared with verapamil. F. The effect of Y-320 on the ATPase activity of P-gp was measured in different concentrations. Data are shown as mean ± SD. Student’s t-test was used for two-group comparisons. CTL, control; PTX+Y-320, combination of paclitaxel and Y-320. Rod, treatment with 5 µM rhodamine 123 for 0.5 h.
Figure 5
Figure 5
The co-administration with Y-320 improves the effectiveness of paclitaxel in Bats-72 xenograft models without additional adverse effects. Nude mice bearing Bats-72 tumors were treated with paclitaxel +/-Y-320. A. Tumor mass compared among four groups with different treatments. B. Tumor volume of the four groups in the process. C. Tumor weight compared among groups at the end of experiments. The inhibition rates of tumor gross in paclitaxel and co-treatment group were calculated compared with the control group. D. Ki-67 immunohistochemical staining (×200) of tumor. E. Body weight of mice at the end of experiment. F, G. Serum ALT and Cr levels measured in each group at the end of experiment. Data are shown as mean ± SD. Student’s t-test was used for two-group comparisons, and multiple-treatment groups were analyzed by one-way ANOVA. N.S., P>0.05; *P<0.05; **P<0.01; CTL, control; PTX+Y-320, combination of paclitaxel and Y-320. IR, inhibition rate.

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