Fluvastatin sensitizes pancreatic cancer cells toward radiation therapy and suppresses radiation- and/or TGF-β-induced tumor-associated fibrosis

Mohapatra, Debendra K.; Das, Biswajit; Suresh, Voddu; Parida, Deepti; Minz, Aliva Prity; Nayak, Usharani; Mohapatra, Amlan Priyadarshee; Swain, Roy; Senapati, Shantibhusan

doi:10.1038/s41374-021-00690-7

Cited by 10 publications

(7 citation statements)

References 48 publications

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“…These compensatory mechanisms in tumor cells lead to different responses to treatment with DNA damage agents, as well as RT (1,48). Both RS and radiation activate a similar DDR pathway, providing the possibility of a synergistic effect of targeting RS with RT (49,50).…”

Section: Cell Cycle Distributionmentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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Section: Cell Cycle Distributionmentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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“…Another study observed that the treatment of zebrafish embryos with flavopiridol, a cyclin D1 inhibitor, enhanced the radiation sensitivity of zebrafish embryos [39]. In the recent past, one of our studies reported fluvastatin as a potential radiosensitizer using zebrafish embryos [17].…”

Section: Zebrafish Model Systemmentioning

confidence: 61%

“…They evaluated the radiosensitizing efficacy of AuNPs and AgNPs in an orthotopic mouse brain tumor model using U125 cells [51]. Our study used the UN-KC-6141 syngeneic mouse subcutaneous pancreatic tumor model and found that fluvastatin sensitized pancreatic cancer toward radiation and inhibited radiation-induced fibrosis [17]. Our study advocates that the mouse model can be used not only for radiation modifiers but also to check the side effects of radiation like fibrosis in tumor stroma.…”

Section: Mouse Modelmentioning

confidence: 77%

“…Targeting a specific pathway or specific molecule is the key to screening the radiosensitizer and radioprotector by cell-based high-throughput screening. Among the targeted pathways are DNA damage and repair pathway [11,12], PI3K-AKT Pathway [13,14], Mevalonate pathway [15][16][17], Mitogen-activated protein kinase (MAPK) Pathway [18,19], and NFκB Pathway [20][21][22] are the most highlighted pathways to screen radiosensitizer or radioprotector by cell-based screening. High-throughput screening of radiosensitizer and radioprotector can also be done through live dead staining, as described in Figure 2.…”

Section: Cell-based High-throughput Screeningmentioning

confidence: 99%

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In-vitro and in-vivo models for the identification and validation of radioprotectors and radiosensitizers

Mohapatra¹,

Mohapatra²,

Sahoo³

et al. 2022

J App Biol Biotech

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the normal cells [4]. Thus, potent radioprotectors for normal cells or radiosensitizers for cancer cells have gained much attention to address radiation-induced challenges depending on the need. The screening procedure of potent radioprotector/radiosensitizer molecules demands a perfect model that may be a cell-based model or an animal model.The demand for animal models has sharply increased to screen potential radioprotectors and radiosensitizers to elucidate the effect of these molecules in different physiological and genetic setups. The search to explore suitable in-vitro and in-vivo models is to be used to screen radiation modifiers and understand the effect of radiation and modifiers in different physiological conditions with different genetic setups. Here, we summarized many of the major other model systems used to assess radioprotectors and radiosensitizers central to radiation therapy or radiation exposure. IN VITRO MODELS Organoid/3D Culture ModelOrganoids are three-dimensional tissue-resembling structures that provide better in vivo tumor architecture and are a convenient model for observing cell-cell interaction in comparison to 2D culture systems [5]. Patient-derived organoids (PDOs) are suitable models for rapid testing of multiple drugs and radiation than the time-consuming

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“…Fluvastatin use in combination with the histone deacetylase inhibitor, vorinostat, induced apoptosis and inhibited cell growth through the activation of AMP-activated protein kinase in renal cancer cells [ 116 ]. Fluvastatin treatment in a murine model of pancreatic cancer also demonstrated a robust anti-tumor effect when used in combination with radiation therapy [ 117 ].…”

Section: Targeting the Mevalonate Pathwaymentioning

confidence: 99%

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

Pereira

Matuszewska

Glogova

et al. 2022

Cancers

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Tumor cells have the ability to co-opt multiple metabolic pathways, enhance glucose uptake and utilize aerobic glycolysis to promote tumorigenesis, which are characteristics constituting an emerging hallmark of cancer. Mutated tumor suppressor and proto-oncogenes are frequently responsible for enhanced metabolic pathway signaling. The link between mutant p53 and the mevalonate (MVA) pathway has been implicated in the advancement of various malignancies, with tumor cells relying heavily on increased MVA signaling to fuel their rapid growth, metastatic spread and development of therapy resistance. Statin drugs inhibit HMG-CoA reductase, the pathway’s rate-limiting enzyme, and as such, have long been studied as a potential anti-cancer therapy. However, whether statins provide additional anti-cancer properties is worthy of debate. Here, we examine retrospective, prospective and pre-clinical studies involving the use of statins in various cancer types, as well as potential issues with statins’ lack of efficacy observed in clinical trials and future considerations for upcoming clinical trials.

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Fluvastatin sensitizes pancreatic cancer cells toward radiation therapy and suppresses radiation- and/or TGF-β-induced tumor-associated fibrosis

Cited by 10 publications

References 48 publications

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

In-vitro and in-vivo models for the identification and validation of radioprotectors and radiosensitizers

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

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