Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma

Abstract

Human papillomavirus (HPV) DNA integrations may affect therapeutic responses in cancers through ATM network-related DNA damage response (DDR). We studied whether cisplatin-induced DDR was altered in human HK-2 renal tubular cells immortalized by HPV16 E6/E7 genes. Cytotoxicity assays utilized thiazolyl blue dye and DDR was identified by gene expression differences, double-strand DNA breaks, ATM promoter activity, and analysis of cell cycling and side population cells. After cisplatin, HK-2 cells showed greater ATM promoter activity indicating activation of this network, but DDR was muted, since little γH2AX was expressed, DNA strand breaks were absent and cells continued cycling. When HK-2 cells were treated with the MDM2 antagonist inducing p53, nutlin-3, or p53 transcriptional activator, tenovin-1, cell growth decreased but cisplatin toxicity was unaffected. By contrast, arsenic trioxide, which by inhibiting wild-type p53-induced phosphatase-1 that serves responses downstream of p53, and by depolymerizing tubulin, synergistically enhanced cisplatin cytotoxicity including loss of SP cells. Our findings demonstrated that HPV16 E6/E7 altered DDR through p53-mediated cell growth controls, which may be overcome by targeting of WIP1 and other processes, and thus should be relevant for treating renal cell carcinoma.

Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration

“…13 This ATM signalling is critical for DNA damage response (DDR) and was involved in chemotherapeutic, as well as APAP toxicity. 14–16 The effect of ATM extended to LR since outcomes after PH worsened in ATM knockout mice. 17 Moreover, ATM signalling is vital for both advancing and restricting cell cycling in a context-specific manner.…”

“…To overcome this difficulty, we used HuH-7 cell line that was derived from human hepatocellular carcinoma, and has been useful for drug studies. 15,16,26 We established aspects of APAP toxicity in HuH-7 cells, including mitochondrial dysfunction, DNA damage and cell death, followed by studies of cell cycle regulation. To address disease-relevance of findings in HuH-7 cells, we verified results in primary human hepatocytes and examined hepatic explants during liver transplantation for APAP-induced ALF.…”

<p>Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment</p>

“…Acute promyelocytic leukemia, 16 renal cancer, prostate cancer, hepatocellular carcinoma, [17][18][19] lung cancer 20,21 As 2 O 3 can induce the accumulation of cellular ROS, causing DNA damage and leading to cell-cycle arrest and apoptosis in various solid tumors. [17][18][19] Resveratrol Osteosarcoma cells, 22 breast cancer, 23 colon cancer, 24 cervical cancer, blood cancer, kidney cancer, liver cancer, bladder cancer, thyroid cancer, esophageal cancer, prostate cancer, brain cancer, gastric cancer, bone cancer, ovarian cancer 25 It can induce apoptosis and inhibit proliferation by modulating the PI3K-Akt-mTOR and MAPK pathways. 22,26,27 Ginsenoside Gambogic acid can induce apoptosis, 46 enhance the accumulation of ROS, 47 and inhibit telomerase activity.…”

The high-risk HPV infection and urinary system tumor

“…The HPV DNA integrated into the human cellular gene exhibits the following activities: leads to inhibiting effect on the vascular endothelial growth factor through E2 gene inactivation and E5 gene; leads to high expression of E6 and E7 proteins; inhibits the activity of P53, retinoblastoma (RB), and other anti-oncogenes; and results in abnormal cell differentiation and activated transcription of telomerase. These activities may be the mechanisms for tumorigenesis [27].…”