Increased Growth-Inhibitory and Cytotoxic Activity of Arsenic Trioxide in Head and Neck Carcinoma Cells with Functional p53 Deficiency and Resistance to EGFR Blockade

Abstract

Background and PurposeMutations in the p53 gene are frequently observed in squamous cell carcinoma of the head and neck region (SCCHN) and have been associated with drug resistance. The potential of arsenic trioxide (ATO) for treatment of p53-deficient tumor cells and those with acquired resistance to cisplatin and cetuximab was determined.Material and MethodsIn a panel of 10 SCCHN cell lines expressing either wildtype p53, mutated p53 or which lacked p53 by deletion the interference of p53 deficiency with the growth-inhibitory and radiosensitizing potential of ATO was determined. The causal relationship between p53 deficiency and ATO sensitivity was evaluated by reconstitution of wildtype p53 in p53-deficient SCCHN cells. Interference of ATO treatment with cell cycle, DNA repair and apoptosis and its efficacy in cells with acquired resistance to cisplatin and cetuximab was evaluated.ResultsFunctional rather than structural defects in the p53 gene predisposed tumor cells to increased sensitivity to ATO. Reconstitution of wt p53 in p53-deficient SCCHN cells rendered them less sensitive to ATO treatment. Combination of ATO with irradiation inhibited clonogenic growth in an additive manner. The inhibitory effect of ATO in p53-deficient tumor cells was mainly associated with DNA damage, G2/M arrest, upregulation of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors and apoptosis. Increased activity of ATO was observed in cetuximab-resistant SCCHN cells whereas cisplatin resistance was associated with cross-resistance to ATO.ConclusionsAddition of ATO to treatment regimens for p53-deficient SCCHN and tumor recurrence after cetuximab-containing regimens might represent an attractive strategy in SCCHN.

Arsenic Trioxide exerts cytotoxic and radiosensitizing effects in pediatric Medulloblastoma cell lines of SHH Subgroup

“…Different point mutations in TP53 binding sites activate paradoxical cellular programs such as cell death by apoptosis or DNA damage response mechanisms 17,18 . Besides, additional experiments using non-malignant cells are essential to assess whether a combination of ATO with radiation therapy has a selective effect in cancer cells, a study in head and neck carcinoma corroborates with our findings 19 . The authors showed that the combination of ATO with irradiation was shown able to reduce colony formation in p53-deficient cells, which was associated with DNA damage, G2/M arrest, and apoptosis 19 .…”

“…Besides, additional experiments using non-malignant cells are essential to assess whether a combination of ATO with radiation therapy has a selective effect in cancer cells, a study in head and neck carcinoma corroborates with our findings 19 . The authors showed that the combination of ATO with irradiation was shown able to reduce colony formation in p53-deficient cells, which was associated with DNA damage, G2/M arrest, and apoptosis 19 . Moreover, the treatment (ATO + irradiation) was already explored in one cerebellar HGNET-BCO SHH+/GLI+ tumor, that achieved six-months tumor remission with therapy's proper safety and tolerability 12 .…”

Arsenic Trioxide Decreases Lymphangiogenesis by Inducing Apoptotic Pathways and Inhibition of Important Endothelial Cell Receptors

“…In line with our findings, recent evidence has shown that ATO can induce apoptosis in a p21-and p53-dependent manner in other tumor models (e.g., hepatocellular carcinoma and glioma) [13,32]. Numerous studies have revealed that ATO can enhance the extrinsic apoptotic pathway by upregulating cell surface death receptors and/or ligands (e.g., Fas and TRAIL), leading to the activation of caspase 8 [33,34]. Furthermore, it has been found that ATO activates the intrinsic apoptotic pathway in different tumor cell lines through mitochondrial membrane disruption, resulting in the release of cytochrome c and the consecutive activation of caspases 3/7 and 9 [35,36].…”

Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies

“…TP53 and CDKN2A were amongst the most frequently mutated genes in the ORL cell lines (94% and 63% respectively). As the mutation status of these genes can add value by improving our overall understanding of tumor biology and influence on drug response [ 21 , 22 ], we validated a sub-set of these mutated genes by Sanger sequencing. To this end, we sequenced exons 4–11 of the TP53 and exons 1–3 of the CDKN2A genes and essentially validated the mutations identified from RNAseq.…”