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

Cipolletti, Manuela; Bartoloni, Stefania; Busonero, Claudia; Parente, Martina; Leone, Stefano; Acconcia, Filippo

doi:10.3390/ijms22062915

Cited by 12 publications

(23 citation statements)

References 40 publications

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“…Finally, we studied the anti-proliferative effects of CHK1 inhibitors ( i.e., AZD, Prexa, MK) in MCF-7 and Y537S tumor cell spheroids [ 7 , 9 ] as well as in alginate-based cultures [ 22 , 23 ] to understand if differences in the effect of these drugs exist in cells grown in 3D structures [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…Tumor spheroid formation was performed as previously reported [ 7 , 9 ]. Briefly, MCF-7 and Y537S cells were seeded (10,000 cells/well) in ultra-low attachment surface 24-well-plates (Sigma-Aldrich) with 1 ml/well in growing condition for 24 h. Next, using an optical microscope, pictures had been taken for each well in untreated conditions ( i.e., time 0).…”

Section: Methodsmentioning

confidence: 99%

“…In this respect, our research group has followed a novel approach to identify additional drugs for primary and MBC treatment building on the assumption that drugs, which do not necessarily bind to the ERα, can induce receptor degradation, and prevent cell proliferation through alternative mechanisms [ 6 ]. After developing a screening platform to contemporarily measure different aspects of ERα signaling as well as cell proliferation [ 7 ], we demonstrated that several Food and Drug Administration (FDA)-approved drugs used for the treatment of diverse diseases can act as ‘anti-estrogen’-like compounds by inducing ERα degradation and blocking cell proliferation in cell lines modeling both the primary and the metastatic LumA phenotypes [ 7 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Clinically relevant CHK1 inhibitors abrogate wild-type and Y537S mutant ERα expression and proliferation in luminal primary and metastatic breast cancer cells

Pescatori

Leone

Cipolletti

et al. 2022

J Exp Clin Cancer Res

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Background Challenges exist in the clinical treatment of luminal estrogen receptor α (ERα)-positive breast cancers (BCs) both to prevent resistance to endocrine therapy (ET) and to treat ET-resistant metastatic BCs (MBC). Therefore, we evaluated if kinases could be new targets for the treatment of luminal primary and MBCs. Methods ~ 170 kinase inhibitors were applied to MCF-7 cells either with adaptative or genetic resistance to ET drugs and both ERα levels and cell proliferation were measured. Robust-Z-score calculation identified AZD7762 (CHK1/CHK2 inhibitor) as a positive hit. Subsequently, Kaplan–Meier analyses of CHK1 and CHK2 impact on ERα-positive BC patients relapse-free-survival (RFS), bioinformatic evaluations of CHK1 and CHK2 expression and activation status as a function of ERα activation status as well as drug sensitivity studies in ERα-positive BC cell lines, validation of the impact of the ATR:CHK1 and ATM:CHK2 pathways on the control of ERα stability and BC cell proliferation via inhibitor- and siRNA-based approaches, identification of the molecular mechanism required for inhibitor-dependent ERα degradation in BC and the impact of CHK1 and CHK2 inhibition on the 17β-estradiol (E2):ERα signaling, synergy proliferation studies between ET-drugs and clinically relevant CHK1 inhibitors in different luminal BC cell lines, were performed. Results A reduced CHK1 expression correlates with a longer RFS in women with ERα-positive BCs. Interestingly, women carrying luminal A BC display an extended RFS when expressing low CHK1 levels. Accordingly, CHK1 and ERα activations are correlated in ERα-positive BC cell lines, and the ATR:CHK1 pathway controls ERα stability and cell proliferation in luminal A BC cells. Mechanistically, the generation of DNA replication stress rather than DNA damage induced by ATR:CHK1 pathway inhibition is a prerequisite for ERα degradation. Furthermore, CHK1 inhibition interferes with E2:ERα signaling to cell proliferation, and drugs approved for clinical treatment of primary and MBC (4OH-tamoxifen and the CDK4/CDK6 inhibitors abemaciclib and palbociclib) exert synergic effects with the CHK1 inhibitors in clinical trials for the treatment of solid tumors (AZD7762, MK8776, prexasertib) in preventing the proliferation of cells modeling primary and MBC. Conclusions CHK1 could be considered as an appealing novel pharmacological target for the treatment of luminal primary and MBCs.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinically relevant CHK1 inhibitors abrogate wild-type and Y537S mutant ERα expression and proliferation in luminal primary and metastatic breast cancer cells

Pescatori

Leone

Cipolletti

et al. 2022

J Exp Clin Cancer Res

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“…Primary cells are the best choice to include in the drug-delivery system and models. Manuela Cipolletti et al [ 18 ] exploited a novel anti-estrogen discovery platform using primary breast cancer cells to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ER signaling to cell proliferation. Yongli Chen et al [ 19 ] developed a microwell array microfluidic system to form diverse spheroids of breast cancer cell T47D and other human cancer cell lines of HepG2 and HCT116 for drug susceptibility testing and offline drug signaling pathways.…”

Section: Various In Vitro Breast Models On a Microfluidic Chipmentioning

confidence: 99%

Diversity Models and Applications of 3D Breast Tumor-on-a-Chip

Song

et al. 2021

Micromachines

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Breast disease is one of the critical diseases that plague females, as is known, breast cancer has high mortality, despite significant pathophysiological progress during the past few years. Novel diagnostic and therapeutic approaches are needed to break the stalemate. An organ-on-chip approach is considered due to its ability to repeat the real conditions found in the body on microfluidic chips, offsetting the shortcomings of traditional 2D culture and animal tests. In recent years, the organ-on-chip approach has shown diversity, recreating the structure and functional units of the real organs/tissues. The applications were also developed rapidly from the laboratory to the industrialized market. This review focuses on breast tumor-on-a-chip approaches concerning the diversity models and applications. The models are summarized and categorized by typical biological reconstitution, considering the design and fabrication of the various breast models. The breast tumor-on-a-chip approach is a typical representative of organ chips, which are one of the precedents in the market. The applications are roughly divided into two categories: fundamental mechanism research and biological medicine. Finally, we discuss the prospect and deficiencies of the emerging technology. It has excellent prospects in all of the application fields, however there exist some deficiencies for promotion, such as the stability of the structure and function, and uniformity for quantity production.

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“…In particular, the readers of this Special Issue will learn about the anti-tumor activity of neosynthesized, natural, and already-available drugs that could be used as new anti-BC drugs. Indeed, the contributing authors have reported the antiproliferative activity of berberine and troglitazone derivatives, resveratrol analogs, atoquavone, clotrimazole, fenticonazole, compounds specifically targeting mitochondrial activity, and valproic acid, as well as NAMPT and carbonic anhydrase IX inhibitors [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”

mentioning

confidence: 99%