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Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms.
Anticancer Res 2018; 38(9):5149-5157AR

Abstract

BACKGROUND/AIM

The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment.

MATERIALS AND METHODS

Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells.

RESULTS

DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID.

CONCLUSION

These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

Authors+Show Affiliations

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea syoon88@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30194162

Citation

Kim, Ji Yeong, et al. "Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms." Anticancer Research, vol. 38, no. 9, 2018, pp. 5149-5157.
Kim JY, Son JY, Lee BM, et al. Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms. Anticancer Res. 2018;38(9):5149-5157.
Kim, J. Y., Son, J. Y., Lee, B. M., Kim, H. S., & Yoon, S. (2018). Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms. Anticancer Research, 38(9), pp. 5149-5157. doi:10.21873/anticanres.12837.
Kim JY, et al. Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms. Anticancer Res. 2018;38(9):5149-5157. PubMed PMID: 30194162.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms. AU - Kim,Ji Yeong, AU - Son,Ji Yeon, AU - Lee,Byung-Mu, AU - Kim,Hyung Sik, AU - Yoon,Sungpil, PY - 2018/08/07/received PY - 2018/08/17/revised PY - 2018/08/20/accepted PY - 2018/9/9/entrez PY - 2018/9/9/pubmed PY - 2018/9/20/medline KW - Donepezil KW - P-gp KW - apoptosis KW - cancer KW - drug resistance KW - repositioning drug KW - sildenafil citrate SP - 5149 EP - 5157 JF - Anticancer research JO - Anticancer Res. VL - 38 IS - 9 N2 - BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment. MATERIALS AND METHODS: Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells. RESULTS: DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID. CONCLUSION: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON. SN - 1791-7530 UR - https://www.unboundmedicine.com/medline/citation/30194162/Aging_related_Repositioned_Drugs_Donepezil_and_Sildenafil_Citrate_Increase_Apoptosis_of_Anti_mitotic_Drug_resistant_KBV20C_Cells_Through_Different_Molecular_Mechanisms_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=30194162 DB - PRIME DP - Unbound Medicine ER -