The Isoxazole Derivative of Usnic Acid Induces an ER Stress Response in Breast Cancer Cells That Leads to Paraptosis-like Cell Death

Pyrczak-Felczykowska, Agnieszka; Reekie, Tristan A.; Jąkalski, Marcin; Hać, Aleksandra; Malinowska, Marcelina; Pawlik, Anna; Ryś, Kamil; Guzow-Krzemińska, Beata; Herman-Antosiewicz, Anna

doi:10.3390/ijms23031802

Cited by 14 publications

(9 citation statements)

References 60 publications

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“…The RNA-seq data of paraptosis strongly supports the expression of the proteins, as mentioned earlier, through its differentially expressed genes (Pyrczak-Felczykowska et al, 2022).…”

Section: Proteasomal Inhibition/er Stressmediated Paraptosissupporting

confidence: 74%

Paraptosis: a unique cell death mode for targeting cancer

Hanson,

Dharan,

P. V.

et al. 2023

Front. Pharmacol.

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Programmed cell death (PCD) is the universal process that maintains cellular homeostasis and regulates all living systems’ development, health and disease. Out of all, apoptosis is one of the major PCDs that was found to play a crucial role in many disease conditions, including cancer. The cancer cells acquire the ability to escape apoptotic cell death, thereby increasing their resistance towards current therapies. This issue has led to the need to search for alternate forms of programmed cell death mechanisms. Paraptosis is an alternative cell death pathway characterized by vacuolation and damage to the endoplasmic reticulum and mitochondria. Many natural compounds and metallic complexes have been reported to induce paraptosis in cancer cell lines. Since the morphological and biochemical features of paraptosis are much different from apoptosis and other alternate PCDs, it is crucial to understand the different modulators governing it. In this review, we have highlighted the factors that trigger paraptosis and the role of specific modulators in mediating this alternative cell death pathway. Recent findings include the role of paraptosis in inducing anti-tumour T-cell immunity and other immunogenic responses against cancer. A significant role played by paraptosis in cancer has also scaled its importance in knowing its mechanism. The study of paraptosis in xenograft mice, zebrafish model, 3D cultures, and novel paraptosis-based prognostic model for low-grade glioma patients have led to the broad aspect and its potential involvement in the field of cancer therapy. The co-occurrence of different modes of cell death with photodynamic therapy and other combinatorial treatments in the tumour microenvironment are also summarized here. Finally, the growth, challenges, and future perspectives of paraptosis research in cancer are discussed in this review. Understanding this unique PCD pathway would help to develop potential therapy and combat chemo-resistance in various cancer.

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“…The RNA-seq data of paraptosis strongly supports the expression of the proteins, as mentioned earlier, through its differentially expressed genes (Pyrczak-Felczykowska et al, 2022).…”

Section: Proteasomal Inhibition/er Stressmediated Paraptosissupporting

confidence: 74%

Paraptosis: a unique cell death mode for targeting cancer

Hanson,

Dharan,

P. V.

et al. 2023

Front. Pharmacol.

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“…Recently, it has been shown that UA isoxazole derivative 2 elevates cytosolic Ca 2+ levels in MCF-7 cells, leading to ER stress [ 19 ]. To elucidate whether derivative 5 acts in a similar way, MCF-7 cells were treated with 5 , and cytosolic Ca 2+ levels were evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we reported the synthesis of UA derivatives that are more cytotoxic toward cancer cells than the parent compound [ 17 , 18 ]. Moreover, the isoxazole derivative of UA induced massive vacuolization of MCF-7 breast cancer cells, which resulted from endoplasmic reticulum (ER) stress and led to paraptosis-like cell death [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo

Gimła,

Pyrczak-Felczykowska,

Malinowska

et al. 2023

Cancer Cell Int

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Background Pancreatic cancer is one of the leading causes of cancer death in Western societies. Its late diagnosis and resistance to chemotherapies result in a high mortality rate; thus, the development of more effective therapies for the treatment of pancreatic cancer is strongly warranted. Usnic acid (UA) is a secondary metabolite of lichens that shows modest antiproliferative activity toward cancer cells. Recently, we reported the synthesis of a UA pyrazole derivative, named 5, which was more active than the parent compound toward cervical cancer cells. Here, its anticancer potential has been evaluated in detail in other cancer cells, particularly pancreatic cancer cells. Methods The impact of UA and derivative 5 on cell viability, morphology, cell cycle, and death was assessed using the MTT test, electron microscopy, flow cytometry, and immunoblotting, respectively. The calcium ions level was detected fluorometrically. In vivo, the anticancer activity of 5 was evaluated in a murine xenograft model. Results Derivative 5 inhibited the viability of different cancer cells. Noncancerous cells were less sensitive. It induced the release of calcium ions from the endoplasmic reticulum (ER) and ER stress, which was manifested by cell vacuolization. It was accompanied by G0/G1 cell cycle arrest and cell death of pancreatic cancer cells. When applied to nude mice with xenografted pancreatic cancer cells, 5 inhibited tumor growth, with no signs of kidney or liver toxicity. Conclusions UA derivative 5 is superior to UA inhibiting the growth and proliferation of pancreatic cancer cells. ER stress exaggeration is a mechanism underlying the activity of derivative 5.

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“…Compound 69 also effectively stopped tumor growth in vivo. 74 The anticancer activity of the amidino-rocaglates 70a-l against MDA-MB-231 breast cancer cells was evaluated in a sulforhodamine B (SRB) assay. The benzofuran derivatives 70c, 70d, and 70l were the most inhibitory active compared with the reference rocaglate-hydroxamate 71.…”

Section: Anticancer Activity Of Dihydrobenzofuran Derivativesmentioning

confidence: 99%