Clotrimazole as a Cancer Drug:A Short Review

Kadavakollu, Samuel; Stailey, C; Cs, Kunapareddy; S, White

doi:10.4172/2161-0444.1000219

Cited by 25 publications

(4 citation statements)

References 41 publications

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“…The anti-cancer effect of Clo and Fenti was already reported [36,37] and we further demonstrate it not only in cells modeling primary tumor but also in cells modeling MBC. In addition to the ability of Clo to interfere with cancer cell metabolism, signaling, and cell cycle [37], we add ERα to the repertoire of the cellular targets of Clo. On the contrary, we show that Fenti could use ERα as one of its cellular targets.…”

Section: Discussionsupporting

confidence: 81%

A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

Cipolletti

Bartoloni

Busonero

et al. 2021

IJMS

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17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.

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Section: Discussionsupporting

confidence: 81%

A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

Cipolletti

Bartoloni

Busonero

et al. 2021

IJMS

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“…Clotrimazole 2, on the other hand, is an imidazole derivative with antifungal activity that is only indicated for topical use due to its toxicity (Figure 1). Similarly to itraconazole, clotrimazole is a synthetic antifungal and its mechanism of action involves the inhibition of sterol biosynthesis [7]. In this sense, Gagini et al [8] reported the effectiveness of the combination of itraconazole with clotrimazole against S. brasiliensis yeasts (the infective form) from feline and human sporotrichosis isolates, suggesting that clotrimazole by itself or in combination with itraconazole is potentially a new option for the treatment of sporotrichosis.…”

Section: Introductionmentioning

confidence: 99%

Development of a Method for the Quantification of Clotrimazole and Itraconazole and Study of Their Stability in a New Microemulsion for the Treatment of Sporotrichosis

et al. 2019

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Sporotrichosis occurs worldwide and is caused by the fungus Sporothrix brasiliensis. This agent has a high zoonotic potential and is transmitted mainly by bites and scratches from infected felines. A new association between the drugs clotrimazole and itraconazole is shown to be effective against S. brasiliensis yeasts. This association was formulated as a microemulsion containing benzyl alcohol as oil, Tween® 60 and propylene glycol as surfactant and cosurfactant, respectively, and water. Initially, the compatibility between clotrimazole and itraconazole was studied using differential scanning calorimetry (DSC), thermogravimetric analysis (TG), Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (PXRD). Additionally, a simple and efficient analytical HPLC method was developed to simultaneously determine the concentration of clotrimazole and itraconazole in the novel microemulsion. The developed method proved to be efficient, robust, and reproducible for both components of the microemulsion. We also performed an accelerated stability study of this formulation, and the developed analytical method was applied to monitor the content of active ingredients. Interestingly, these investigations led to the detection of a known clotrimazole degradation product whose structure was confirmed using NMR and HRMS, as well as a possible interaction between itraconazole and benzyl alcohol.

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“…Several reports have indicated that clotrimazole has anti-cancer properties by decreasing hexokinase (HK) binding to the outer mitochondrial membrane, detaching phosphofructokinase-1 (PFK-1) and aldolase from the cytoskeleton, and by interfering with Ca2+ metabolism and blockage of the Ca2+ activated potassium channel 52 53 54 55 56 . Motawi et al .…”

Section: Discussionmentioning

confidence: 99%

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

Segura‐Cabrera

Tripathi

Zhang

et al. 2017

Sci Rep

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Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.

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Clotrimazole as a Cancer Drug:A Short Review

Cited by 25 publications

References 41 publications

A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

Development of a Method for the Quantification of Clotrimazole and Itraconazole and Study of Their Stability in a New Microemulsion for the Treatment of Sporotrichosis

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

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