Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma <i>in vitro</i> and <i>in vivo</i>

Hasanovic, Anida; Ruggiero, Carmen; Jung, Sara; Rapa, Ida; Signetti, Laurie; Hadj, Monia Ben; Terzolo, Massimo; Beuschlein, Felix; Volante, Marco; Hantel, Constanze; Lalli, Enzo; Mus‐Veteau, Isabelle

doi:10.1002/ijc.31296

Cited by 22 publications

(53 citation statements)

References 43 publications

(52 reference statements)

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“…We previously showed that Ptch1 drug efflux inhibition enhanced the cytotoxicity of dxr against adrenocortical carcinoma cells, but also that of cisplatin, another well known chemotherapeutic drug [19], suggesting that both cisplatin and dxr are substrates of Ptch1 [16]. Therefore, we tested the effect of sPAH on the cytotoxicity of cisplatin in the melanoma cell lines MeWo and A375.…”

Section: Spah Enhances the Sensitivity Of Melanoma Cells To Cisplatinmentioning

confidence: 99%

Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma

Signetti

Elizarov

Simsir

et al. 2020

Cancers

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Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma.

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Section: Spah Enhances the Sensitivity Of Melanoma Cells To Cisplatinmentioning

confidence: 99%

Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma

Signetti

Elizarov

Simsir

et al. 2020

Cancers

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“…According to a review article from Papadopoulos and co-workers [ 43 ], Ptch1 is also upregulated in colorectal cancers. Further, immunohistochemical (IHC) analysis on adrenocortical carcinoma (ACC) samples from 70 patients showed that Ptch1 was expressed in ACC tumor tissues from all 70 patients [ 44 ]. Finally, Ptch1 has been proposed to be an early marker for gastric and thyroid cancers [ 45 , 46 ].…”

Section: The Hh Receptor Ptch1 Is Overexpressed In Many Aggressivementioning

confidence: 99%

“…The hypothesis that Ptch1 could be a multidrug transporter involved in chemotherapy resistance has been strongly strengthened by the observation, using Ptch1-silencing RNA, that doxorubicin efflux from the human cell line H295R, which was isolated from a patient diagnosed with an adrenocortical carcinoma (ACC), mainly occurs through Ptch1 and not through ABC transporters such as P-gp [ 44 ]. Notably, doxorubicin is one of the three chemotherapeutic agents that is included in the gold standard ACC therapy which often fails due to resistance to the treatment, leading to poor overall patient survival [ 74 , 75 ].…”

Section: Ptch1 Is a Multidrug Transporter Involved In Chemotherapymentioning

confidence: 99%

“…The screening of a collection of 1200 small drug and drug-like molecules allowed the discovery of a second inhibitor of Ptch1 drug efflux activity. In a recent study, Hasanovic and co-workers [ 44 ] showed that methiothepin, a serotonin transporter antagonist [ 82 , 83 ], significantly enhances the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on ACC cells by inhibiting the doxorubicin efflux activity of Ptch1. They observed the same effect of methiothepin on cells that had been rendered resistant to doxorubicin.…”

Section: Inhibition Of Ptch1 Drug Efflux Activity Increases Chemotmentioning

confidence: 99%

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Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency

Hasanovic

Mus‐Veteau

2018

Cells

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One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and thereby increase classical chemotherapy efficacy, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitors due to toxicity issues. Hedgehog signaling is aberrantly activated in many cancers, and has been shown to be involved in chemotherapy resistance. Recent studies showed that the Hedgehog receptor Ptch1, which is over-expressed in many recurrent and metastatic cancers, is a multidrug transporter and it contributes to the efflux of chemotherapeutic agents such as doxorubicin, and to chemotherapy resistance. Remarkably, Ptch1 uses the proton motive force to efflux drugs, in contrast to ABC transporters, which use ATP hydrolysis. Indeed, the “reversed pH gradient” that characterizes cancer cells, allows Ptch1 to function as an efflux pump specifically in cancer cells. This makes Ptch1 a particularly attractive therapeutic target for cancers expressing Ptch1, such as lung, breast, prostate, ovary, colon, brain, adrenocortical carcinoma, and melanoma. Screening of chemical libraries have identified several molecules that are able to enhance the cytotoxic effect of different chemotherapeutic agents by inhibiting Ptch1 drug efflux activity in different cancer cell lines that endogenously over-express Ptch1. In vivo proof of concept has been performed in mice where combining one of these compounds with doxorubicin prevented the development of xenografted adrenocortical carcinoma tumors more efficiently than doxorubicin alone, and without obvious undesirable side effects. Therefore, the use of a Ptch1 drug efflux inhibitor in combination with classical or targeted therapy could be a promising therapeutic option for Ptch1-expressing cancers.

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“…Among several mechanisms that may lead to the development of MDR, the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 (P-glycoprotein, MDR1: multidrug resistance protein 1), ABCC1 (MRP1: multidrug resistance-associated protein 1), and ABCG2 (BCRP: breast cancer resistance protein) proteins seems to prevail [3,4]. It was recently reported that non-ABC transporters such as Hedgehog receptor Patched were also engaged in doxorubicin (Dox) efflux and conferred Dox resistance to cancer cells [5,6]. ABCB1 is a transporter that utilizes the energy gained from the hydrolysis of ATP to pump many structurally variable substrates (including xenobiotics and chemotherapeutics) out of the cell [7].…”

Section: Introductionmentioning

confidence: 99%

Organosilicon Compounds, SILA-409 and SILA-421, as Doxorubicin Resistance-Reversing Agents in Human Colon Cancer Cells

et al. 2020

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Multidrug resistance (MDR) that occurs in cancer cells constitutes one of the major reasons for chemotherapy failure. The main molecular mechanism of MDR is overexpression of protein transporters from the ATP-binding cassette (ABC) superfamily, such as ABCB1 (multidrug resistance protein 1 (MDR1), P-glycoprotein). At the expense of ATP hydrolysis, ABCB1 pumps a diverse range of substrates (including anticancer drugs) out of the cell, thereby reducing their intracellular concentration. In the present study, the ability of two patented disiloxanes (SILA-409 and SILA-421) to reverse drug resistance in human colon adenocarcinoma cell lines LoVo and LoVo/Dx was investigated. It was demonstrated that both compounds in concentrations of 0.5–1 µM strongly increased the sensitivity of LoVo/Dx cells to doxorubicin. By means of an accumulation test in which rhodamine 123 was used as an ABCB1 substrate analogue, both organosilicon compounds were also shown to inhibit ABCB1 transport activity. The intracellular accumulation of doxorubicin was also increased, and more drug entered the cellular nuclei of resistant cells in the presence of the studied compounds. In conclusion, both SILA-409 and SILA-421 were demonstrated to be effective MDR reversal agents in resistant human colon cancer cells.

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Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo

Cited by 22 publications

References 43 publications

Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma

Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma

Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency

Organosilicon Compounds, SILA-409 and SILA-421, as Doxorubicin Resistance-Reversing Agents in Human Colon Cancer Cells

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