Piperlongumine and p53-reactivator APR-246 selectively induce cell death in HNSCC by targeting GSTP1

Abstract

TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC. PRIMA-1 (p53-Reactivation and Induction of Massive Apoptosis-1) and its methylated analogue PRIMA-1Met (also called APR-246) were found to be able to reestablish the DNA-binding activity of p53 mutants and reinstate the functions of WT p53. Herein we report that piperlongumine (PL), an alkaloid isolated from Piper longum L., synergizes with APR-246 to selectively induce apoptosis and autophagic cell death in HNSCC cells, whereas primary and immortalized mouse embryonic fibroblasts (MEFs) and spontaneously immortalized non-tumorigenic human skin keratinocytes (HaCat) are spared from the damage by the cotreatment. Interestingly, PL-sensitized HNSCC cells to APR-246 are TP53 mutation-independent. Instead, we demonstrated that glutathione S-transferase pi 1 (GSTP1), a GST family member that catalyzes the conjugation of GSH with electrophilic compounds to fulfill its detoxification function, is highly expressed in HNSCC tissues. Administration of PL and APR-246 significantly suppresses GSTP1 activity, resulting in the accumulation of ROS, depletion of GSH, elevation of GSSG, and DNA damage. Ectopic expression of GSTP1 or pretreatment with antioxidant N-acetyl-L-cysteine (NAC) abrogates the ROS elevation and decreases DNA damage, apoptosis, and autophagic cell death prompted by PL/APR-246. In addition, administration of PL and APR-246 impedes UMSCC10A xenograft tumor growth in SCID mice. Taken together, our data suggest that HNSCC cells are selectively sensitive to the combination of PL and APR-246 due to a remarkably synergistic effect of the cotreatment in the induction of ROS by suppression of GSTP1.

Vitexin compound 1, a novel extraction from a Chinese herb, suppresses melanoma cell growth through DNA damage by increasing ROS levels

“…Although ROS facilitates the progression of cancer to some extent, the accumulation of ROS reaches a threshold and then causes cell death [ 23 ]. Therefore, increasing the ROS level to induce cancer cell death is a well-known anticancer strategy [ 38 – 40 ]. Evidence shows that pharmaceutical compounds extracted from plants, such as resveratrol, levistolide A and piperlongumine, induce apoptosis through DNA toxicity by the induction of intracellular ROS [ 40 – 42 ].…”

“…Therefore, increasing the ROS level to induce cancer cell death is a well-known anticancer strategy [ 38 – 40 ]. Evidence shows that pharmaceutical compounds extracted from plants, such as resveratrol, levistolide A and piperlongumine, induce apoptosis through DNA toxicity by the induction of intracellular ROS [ 40 – 42 ]. In this study, we measured the level of intracellular ROS in melanoma after VB1 treatment, and the results showed that VB1 significantly increases ROS levels, which indicates that the cells were under high oxidative stress.…”

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

“…Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. Potent cytotoxicity, genotoxicity, antitumor, antiangiogenic and antimetastatic properties, in addition to presenting adequate bioavailability and safety profile have been attributed for this molecule and its derivatives [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] . Although its cytotoxic properties have been known for over three decades, the great interest in this molecule has arisen after its cytotoxicity and ability to induce the production of reactive oxygen species (ROS) selectively in cancer cells were described [11] , [12] .…”

The Application of Next-Generation Sequencing to Define Factors Related to Oral Cancer and Discover Novel Biomarkers

“…The cysteine-binding PRIMA-1 and APR-246 induce apoptosis through caspase activation [ 75 ]. The efficacy of PRIMA-1 and APR-246 has been demonstrated in many studies investigating various malignancies, but only a few studies have practiced them on OSCC/HNSCC treatment so far [ 76 , 77 ]. Although the studies have confirmed the p53 restoring ability of PRIMA-1 and APR-246, experimental outcomes suggest that their anti-cancer characteristics might be independent of p53 restoration [ 78 ].…”