Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells

Roberti, Marinella; Schipani, Fabrizio; Bagnolini, Greta; Milano, Domenico; Giacomini, Elisa; Falchi, Federico; Balboni, Alice; Manerba, Marcella; Farabegoli, Fulvia; Franco, Francesca; Robertson, Janet; Minucci, Saverio; Pallavicini, Isabella; Stefano, Giuseppina Di; Girotto, Stefania; Pellicciari, Roberto; Cavalli, Andrea

doi:10.1016/j.ejmech.2019.01.008

Cited by 36 publications

(49 citation statements)

References 30 publications

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“…Then, the DNA damage repair pathway was activated, and the ATM/Chk2/BRCA1 were all phosphorylated to work . However, the expression of p‐BRCA1 and Rda51 was dramatically decreased after adapalene treatment in our study . Therefore, we guessed that the activation of DNA damage and inhibition of DNA repair could both contribute to the apoptosis of HaCat cells after the treatment of adapalene.…”

Section: Discussionmentioning

confidence: 99%

The third‐generation retinoid adapalene triggered DNA damage to induce S‐phase arrest in HaCat cells

Wang

et al. 2019

Fundamemntal Clinical Pharma

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Epidermal proliferative diseases consisted of a series of common skin diseases, most of which were recurrent chronic skin diseases, and had greatly negative influence on the life quality of patient. Retinoids exhibited vital roles in the treatment of many skin diseases. Our recent study demonstrated that adapalene significantly inhibited the growth of HaCat cells, and the inhibitory activity was stronger than other retinoids, such as all-trans-retinoic acid, acitretin, isotretinoin, tazarotene, and bexarotene. Further study showed that adapalene suppressed the colony formation of HaCat cells, and it dramatically triggered S-phase arrest and apoptosis, rather than G1 phase arrest which was reported in other retinoids in several studies. Additionally, adapalene treatment greatly upregulated the protein expression of DNA damage marker c-H2AX, which was in accord with the results of the elongation of tail moment by comet electrophoresis analysis. Moreover, DNA damage was triggered and DNA repair was suppressed synchronously with adapalene treatment, which accounted for the mechanism of S-phase arrest induced by adapalene. In summary, our recent work demonstrated that adapalene showed strong antiproliferation activity in HaCat cells and could be an alternative agent for the epidermal proliferative disease. I N T R O D U C T I O NEpidermal proliferative diseases were a large class of dermatosis which contained various common and uncommon skin diseases such as psoriasis, verruca vulgaris, pityriasis rubra pilaris, and palmoplantar keratoderma. Moreover, most of the epidermal proliferative diseases were recurrent chronic skin diseases which seriously affected the life quality of patients. Long-term clinical practice showed that oral or topical retinoids were a kind of effective and relatively safe therapy for these diseases. Retinoids were a serious of natural or synthetic derivatives of retinol which played vital roles in the differentiation and proliferation of epidermal cells, and made great influence on the formation, development and maintenance of normal epidermis. In addition, retinoids were also widely used for the experiments of diverse human cancers due to their influences on the cell proliferation and apoptosis of multiple tumor cells [1]. Currently, the commonly used retinoids were alltrans-retinoic acid (ATRA), acitretin, isotretinoin, and tazarotene [2][3][4][5][6][7][8]. However, repeated and long-term use of these drugs often caused a lot of adverse reactions like allergic reaction, dry skin, piercing, photosensitivity, and skin infection. More importantly, the teratogenicity of retinoids could not be ignored. Hence, the high-efficiency and low-adverse-reaction drugs remained the pursuit of the clinical application.Adapalene, the third-generation synthetic retinoic acid, was hardly absorbed into blood circulation and ª 2019 Soci et e Franc ßaise de Pharmacologie et de Th erapeutique 380

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Section: Discussionmentioning

confidence: 99%

The third‐generation retinoid adapalene triggered DNA damage to induce S‐phase arrest in HaCat cells

Wang

et al. 2019

Fundamemntal Clinical Pharma

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“…Specically, following DNA-end resection, BRCA2 directs RAD51 lament nucleation onto single-stranded DNA (ssDNA), which catalyzes a strand exchange reaction to initiate HR repair. 54,55 We hence measured the levels of RAD51 and BRCA2 in A549/DDP cells aer exposure to complexes 1 and 2 or CDDP to evaluate their impact on the HR ability. As shown in Fig.…”

Section: Expression Of Hr Proteins Rad51 and Brca2mentioning

confidence: 99%

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

et al. 2020

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“…This compound specifically works on those cancer cells where RAD51 is overexpressed, sensitizing them to chemo/radiotherapy and PARP inhibitors [132,133]. IBR120 is an inhibitor that disrupts RAD51 interaction with BRCA2 sensitizing cancer cells to IR [134,135]. Finally, CYT-0851 is a compound that reduced RAD51 migration to damaged DNA ends [125].…”

Section: Combination Of Dsb Inducers and Dsb-repair Proteins Inhibitimentioning

confidence: 99%

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

Lodovichi

Cervelli

Pellicioli

et al. 2020

IJMS

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Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.

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Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells

Cited by 36 publications

References 30 publications

The third‐generation retinoid adapalene triggered DNA damage to induce S‐phase arrest in HaCat cells

The third‐generation retinoid adapalene triggered DNA damage to induce S‐phase arrest in HaCat cells

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

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