Highly Halaven-resistant KBV20C Cancer Cells Can Be Sensitized by Co-treatment with Fluphenazine

Cheon, Ji Hyun; Lee, Byung Mu; Kim, Hyung Sik; Yoon, Sungpil

doi:10.21873/anticanres.11172

Cited by 21 publications

(49 citation statements)

References 27 publications

(44 reference statements)

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“…Comparison among verapamil, CEP-33779, and XL019 showed that all three effectively sensitized KBV20C cells to vincristine. Considering that verapamil is a representative and wellknown P-gp inhibitor (17,20,21), both JAK2 inhibitors should be regarded as P-gp inhibitors. Thus, we assume that in the clinic, both CEP-33779 and XL019 could be applied to sensitize not only JAK2-overexpressing cancer cells, but also P-gp-overexpressing cancer cells in heterogeneous cancer tissue populations such as TNBC.…”

Section: Discussionmentioning

confidence: 99%

“…Human oral squamous carcinoma cell line KB and its multidrugresistant subline KBV20C were obtained from Dr. Yong Kee Kim (College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea) and have been previously described (17,18). All cell lines were cultured in RPMI-1640 containing 10% fetal bovine serum, 100 U/ml penicillin, and 100 μg/ml streptomycin (WelGENE, Daegu, Republic of Korea).…”

Section: Methodsmentioning

confidence: 99%

“…In the next phase of our investigation, we tested the efficacy of XL019 as a P-gp inhibitor to sensitize KBV20C cells to vincristine-induced mitotic arrest. We compared the effects of XL019 with those of the well-known P-gp inhibitor, verapamil (17,18). As shown in Figure 3A, 5 μM XL019 or 10 μM verapamil similarly sensitized the cells to vincristine, reducing KBV20C cell viability, and suggesting that a lower dose of XL019 is sufficient and more effective at sensitizing P-gpoverexpressing resistant cancer cells than the P-gp inhibitor verapamil.…”

Section: Co-treatment With Xl019 Increases the Sensitization Of Vincrmentioning

confidence: 99%

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P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression

Cheon

Kim

Lee

et al. 2017

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The present study was designed to identify conditions that could increase the sensitivity of resistant cancer cells to antimitotic drugs. We investigated whether a Janus kinase 2 (JAK2) inhibitor used in clinical trials, XL019, sensitizes antimitotic drug-resistant KBV20C cells. XL019 reduced cellular viability and increased apoptosis in vincristine-treated KBV20C cells, independently of the JAK/signal transducer and activator of transcription (STAT) pathway. Based on the ATP-binding cassette protein B1 [ABCB1, P-glycoprotein (P-gp)] inhibitory assay, we demonstrated that XL019 functions as a P-gp inhibitor in drug-resistant KBV20C cells. Considering that another JAK2 inhibitor, CEP-33779, also inhibited P-gp and sensitized drug-resistant cancer cells in a previous study, we concluded that JAK2 inhibitors can be used as P-gp inhibitors in drug-resistant cancer cells. Fluorescence-activated cell sorting, western blot, and annexin V analyses were used to further investigate the mechanism of action of XL019 in vincristine-treated KBV20C cells. XL019 induced early apoptosis of KBV20C cells in response to vincristine treatment via increased G phase arrest. Moreover, G phase arrest and apoptosis of cells co-treated with vincristine and XL019 resulted from the up-regulation of phosphorylated retinoblastoma protein (pRb), p21, and the DNA-damage protein, phosphorylated H2A histone family, member X (pH2AX). Additionally, the P-gp-inhibitory effect of XL019 was less than that of CEP-33779, and a more than 2-fold higher dose was required to sensitize vincristine-treated KBV20C cells. Furthermore, lower doses of XL019 were required to sensitize KBV20C cells to a degree similar to that obtained with the established P-gp inhibitor verapamil, suggesting that XL019 has higher specificity than verapamil. Our results showed that JAK2 inhibitors inhibited P-gp action via a direct binding mechanism, which was similar to that of verapamil. These findings indicate that JAK2 inhibitors may be promising therapeutics for the treatment of cancer that is resistant to antimitotic drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Co-treatment With Xl019 Increases the Sensitization Of Vincrmentioning

confidence: 99%

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P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression

Cheon

Kim

Lee

et al. 2017

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“…Multidrug-resistant KBV20C human oral squamous carcinoma can be adapted to eribulin at 500-fold higher than that used to treat their drug sensitive parental counterparts indicating that eribulin may be effectively pumped out by ABCB1. Thioridazine is able to sensitize eribulin-resistant KBV20C cells, moreover, the combined effect of eribulin and thioridazine resulted in G 2 arrest (70). In another study, ABCB1 of MDR mouse T-lymphoma cells was also inhibited by thioridazine (71).…”

Section: Antitumor Effectmentioning

confidence: 99%

Possible Biological and Clinical Applications of Phenothiazines

Varga

Csonka

et al. 2017

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Abstract. Phenothiazines have been used in many areasPhenothiazines are unanimously one of the most versatile compounds from the view of biological activity. Since their discovery, new exploitable pharmacological properties have emerged from time to time; thus, they have an important role in many areas of medicine and beyond. This is why phenothiazines are basic compounds in pharmacology. The history of these compounds goes back to the second half of the 19th century, when a German chemist, Heinrich August Bernthsen began to study the structure of methylene blue, which was first synthesized in 1876 by Heinrich Caro. In 1885, two years after Bernthsen first managed to produce phenothiazine, he also succeeded in describing the structure of methylene blue (1). At the same time, Paul Ehrlich began to investigate the possible therapeutic use of methylene blue in malaria infections, which he first published in 1891 (2). Due to this, methylene blue was often prescribed for patients with malaria in the subsequent period (3).Research conducted in the 1930s and '40s proved the potential wide use of phenothiazines. The insecticidal (4), antihelmintic (5, 6), and antibacterial (7) effects of the compound were detected; however, it was not widely used for these purposes. In the 1940s, another novel phenothiazine derivative, namely promethazine was brought to the forefront of attention; it was investigated by Paul Charpentier at the Rhone-Poulenc laboratory in Paris (8). It was shown that promethazine had an antihistamine effect (9), which was later used in the therapy of allergic diseases and in anesthesia (10,11). A few years later in the same laboratory, chlorpromazine was discovered, which has strong anxiolytic and antipsychotic effect along with its antihistaminic effect (12). Psychiatry fully exploited this feature in psychotic patients (13), which resulted in the almost complete emptying of psychiatric hospitals in the 1950s. As a result, the discovery of chlorpromazine and the beginning of its use as an antipsychotic are considered the beginning of modern psychiatry and psychopharmacology.Since then, several antipsychotic phenothiazine compounds have been used in clinical practice, although research conducted in the last couple of decades indicated that phenothiazine compounds could have an important role in other fields of medicine as well, such as in the treatment of tumorous, infectious, or neurodegenerative diseases (3). 5983

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“…Therefore, we performed this study to increase our understanding of the mechanisms associated with sensitization of HAL-resistant KBV20C oral cancer cells overexpressing P-gp (16). Mainly, we focused on identifying specific P-gp inhibitors for sensitizing highly HAL-resistant KBV20C cells at low doses.…”

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confidence: 99%

Highly Eribulin-resistant KBV20C Oral Cancer Cells Can Be Sensitized by Co-treatment with the Third-generation P-Glycoprotein Inhibitor, Elacridar, at a Low Dose

Park

Son

Lee

et al. 2017

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These results suggest that highly HAL-resistant cancer cells can be sensitized with cyclosporine A or elacridar, specific P-gp inhibitors that exert their effects at a low dose. These findings provide important information regarding the sensitization of highly HAL-resistant cells with selective P-gp inhibitors and indicate that elacridar may be used to treat such highly HAL-resistant cancer cells.

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Highly Halaven-resistant KBV20C Cancer Cells Can Be Sensitized by Co-treatment with Fluphenazine

Cited by 21 publications

References 27 publications

P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression

P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression

Possible Biological and Clinical Applications of Phenothiazines

Highly Eribulin-resistant KBV20C Oral Cancer Cells Can Be Sensitized by Co-treatment with the Third-generation P-Glycoprotein Inhibitor, Elacridar, at a Low Dose

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