Tags

Type your tag names separated by a space and hit enter

RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems.
Redox Biol. 2017 10; 13:219-227.RB

Abstract

Reactivation of p53 and induction of tumor cell apoptosis (RITA) is a small molecule that blocks p53-MDM2 interaction, thereby reactivating p53 in tumors. RITA can induce exclusive apoptosis in cancer cells independently of the p53 pathway; however, the resistance of cancer cells remains a major drawback. Here, we found a novel resistance mechanism of RITA treatment and an effective combined treatment to overcome RITA resistance in head and neck cancer (HNC) cells. The effects of RITA and 3-methyladenine (3-MA) were tested in different HNC cell lines, including cisplatin-resistant and acquired RITA-resistant HNC cells. The effects of each drug alone and in combination were assessed by measuring cell viability, apoptosis, cell cycle, glutathione, reactive oxygen species, protein expression, genetic inhibition of p62 and Nrf2, and a mouse xenograft model of cisplatin-resistant HNC. RITA induced apoptosis of HNC cells at different levels without significantly inhibiting normal cell viability. Following RITA treatment, RITA-resistant HNC cells exhibited a sustained expression of other autophagy-related proteins, overexpressed p62, and displayed activation of the Keap1-Nrf2 antioxidant pathway. The autophagy inhibitor 3-MA sensitized resistant HNC cells to RITA treatment via the dual inhibition of molecules related to the autophagy and antioxidant systems. Silencing of the p62 gene augmented the combined effects. The effective antitumor activity of RITA plus 3-MA was also confirmed in vivo in mouse xenograft models transplanted with resistant HNC cells, showing increased oxidative stress and DNA damage. The results indicate that RITA plus 3-MA can help overcome RITA resistance in HNC cells.

CONDENSED ABSTRACT

This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual inhibition of autophagy and antioxidant systems in vitro and in vivo.

Authors+Show Affiliations

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: rohjl@amc.seoul.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28582730

Citation

Shin, Daiha, et al. "RITA Plus 3-MA Overcomes Chemoresistance of Head and Neck Cancer Cells Via Dual Inhibition of Autophagy and Antioxidant Systems." Redox Biology, vol. 13, 2017, pp. 219-227.
Shin D, Kim EH, Lee J, et al. RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems. Redox Biol. 2017;13:219-227.
Shin, D., Kim, E. H., Lee, J., & Roh, J. L. (2017). RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems. Redox Biology, 13, 219-227. https://doi.org/10.1016/j.redox.2017.05.025
Shin D, et al. RITA Plus 3-MA Overcomes Chemoresistance of Head and Neck Cancer Cells Via Dual Inhibition of Autophagy and Antioxidant Systems. Redox Biol. 2017;13:219-227. PubMed PMID: 28582730.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems. AU - Shin,Daiha, AU - Kim,Eun Hye, AU - Lee,Jaewang, AU - Roh,Jong-Lyel, Y1 - 2017/06/01/ PY - 2017/05/08/received PY - 2017/05/28/revised PY - 2017/05/30/accepted PY - 2017/6/6/pubmed PY - 2018/7/6/medline PY - 2017/6/6/entrez KW - 3-methyladenine KW - Autophagy KW - Head and neck cancer KW - RITA KW - p62 SP - 219 EP - 227 JF - Redox biology JO - Redox Biol VL - 13 N2 - : Reactivation of p53 and induction of tumor cell apoptosis (RITA) is a small molecule that blocks p53-MDM2 interaction, thereby reactivating p53 in tumors. RITA can induce exclusive apoptosis in cancer cells independently of the p53 pathway; however, the resistance of cancer cells remains a major drawback. Here, we found a novel resistance mechanism of RITA treatment and an effective combined treatment to overcome RITA resistance in head and neck cancer (HNC) cells. The effects of RITA and 3-methyladenine (3-MA) were tested in different HNC cell lines, including cisplatin-resistant and acquired RITA-resistant HNC cells. The effects of each drug alone and in combination were assessed by measuring cell viability, apoptosis, cell cycle, glutathione, reactive oxygen species, protein expression, genetic inhibition of p62 and Nrf2, and a mouse xenograft model of cisplatin-resistant HNC. RITA induced apoptosis of HNC cells at different levels without significantly inhibiting normal cell viability. Following RITA treatment, RITA-resistant HNC cells exhibited a sustained expression of other autophagy-related proteins, overexpressed p62, and displayed activation of the Keap1-Nrf2 antioxidant pathway. The autophagy inhibitor 3-MA sensitized resistant HNC cells to RITA treatment via the dual inhibition of molecules related to the autophagy and antioxidant systems. Silencing of the p62 gene augmented the combined effects. The effective antitumor activity of RITA plus 3-MA was also confirmed in vivo in mouse xenograft models transplanted with resistant HNC cells, showing increased oxidative stress and DNA damage. The results indicate that RITA plus 3-MA can help overcome RITA resistance in HNC cells. CONDENSED ABSTRACT: This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual inhibition of autophagy and antioxidant systems in vitro and in vivo. SN - 2213-2317 UR - https://www.unboundmedicine.com/medline/citation/28582730/RITA_plus_3_MA_overcomes_chemoresistance_of_head_and_neck_cancer_cells_via_dual_inhibition_of_autophagy_and_antioxidant_systems_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2317(17)30343-9 DB - PRIME DP - Unbound Medicine ER -