The Novel Curcumin Derivative 1g Induces Mitochondrial and ER-Stress-Dependent Apoptosis in Colon Cancer Cells by Induction of ROS Production

Wang, Hao; Xu, Yan; Sun, Jialin; Sui, Zhongguo

doi:10.3389/fonc.2021.644197

Cited by 15 publications

(14 citation statements)

References 49 publications

(61 reference statements)

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“…For example, the inhibition of PERK prevented CHOP10 upregulation and the initiation of apoptosis in colon cancer cells treated with the dihydroartemisinin, NSC735847 [ 40 ]. In a different study, blockade of PERK inhibited apoptosis in colorectal cancer cells exposed to a derivative of the natural compound, curcumin [ 41 ]. Similar to these findings, we report ER stress-mediated apoptosis was propagated through PERK in 15d-PMJ 2 treated cells as the blockade of PERK (GSK2606141) and inactivation of downstream eIF2α (salubrinal) prevented cell death.…”

Section: Discussionmentioning

confidence: 99%

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

et al. 2022

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Melanoma is the deadliest form of skin cancer in the US. Although immunotherapeutic checkpoint inhibitors and small-molecule kinase inhibitors have dramatically increased the survival of patients with melanoma, new or optimized therapeutic approaches are still needed to improve outcomes. 15-deoxy-Δ 12,14 -prostamide J 2 (15d-PMJ 2 ) is an investigational small-molecule that induces ER stress-mediated apoptosis selectively in tumor cells. Additionally, 15d-PMJ2 reduces melanoma growth in vivo . To assess the chemotherapeutic potential of 15d-PMJ 2 , the current study sought to uncover molecular pathways by which 15d-PMJ 2 exerts its antitumor activity. B16F10 melanoma and JWF2 squamous cell carcinoma cell lines were cultured in the presence of pharmacological agents that prevent ER or oxidative stress as well as Ca 2+ channel blockers to identify mechanisms of 15d-PMJ 2 cell death. Our data demonstrated the ER stress protein, PERK, was required for 15d-PMJ 2 -induced death. PERK activation triggered the release of ER-resident Ca 2+ through an IP 3 R sensitive pathway. Increased calcium mobilization led to mitochondrial Ca 2+ overload followed by mitochondrial permeability transition pore (mPTP) opening and the deterioration of mitochondrial respiration. Finally, we show the electrophilic double bond located within the cyclopentenone ring of 15d-PMJ 2 was required for its activity. The present study identifies PERK/IP3R/mPTP signaling as a mechanism of 15d-PMJ 2 antitumor activity.

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Section: Discussionmentioning

confidence: 99%

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

et al. 2022

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“…Similar studies have been made with curcumin alone and its derivatives. Wang et al (2021) [ 34 ] recently reported one molecule with potential activity in colon cancer cells (HCT116 and HT29), causing changes in mitochondrial membrane potential. In addition, Agarwal and colleagues (2018) [ 35 ] reported that the treatment with curcumin alone induced significant changes in the mitochondrial membrane potential of HT29 cells in a dose- and time-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

Proapoptotic Effect and Molecular Docking Analysis of Curcumin–Resveratrol Hybrids in Colorectal Cancer Chemoprevention

et al. 2022

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Different hybrids based on curcumin and resveratrol were previously synthesized and characterized by spectroscopic techniques. The most active molecules (3a, 3e, 3i, and 3k) were evaluated in vitro as an approach to determine the possible mechanism of action of the hybrids. The results indicated that the evaluated curcumin/resveratrol hybrids induce mitochondrial instability in SW620 and SW480 cells. Moreover, these molecules caused a loss in membrane integrity, suggesting an apoptotic process mediated by caspases after the treatment with compounds 3i (SW480) and 3k (SW620). In addition, the results suggest that the mechanism of action of the hybrids could be independent of the p53 status. Furthermore, hybrids 3e and 3i caused G0/G1 phase arrest, which highlights the potential of these molecules not only as cytotoxic but also as cytostatic compounds. Hybrids 3e and 3i caused a negative modulation of the matrix metalloproteinase 7 (MMP7) on SW480 cells. These curcumin resveratrol hybrids could be potential candidates for further investigations in the search for potential chemopreventive agents, even in those cases with resistance to conventional chemotherapy because of the lack of p53 expression or function. Molecular docking simulations showed that compounds 3e, 3i, and 3k bind efficiently to proapoptotic human caspases 3/7 proteins, as well as human MMP-7 and p53, which, in turn, could explain at the molecular level the in vitro cytotoxic effect of these compounds in SW480 and SW620 colon cancer cell lines.

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“…For example, Zhang et al [43] reported that libertellenone H treatment significantly increased intracellular ROS generation and induced apoptosis in human pancreatic cancer cells in a ROS-dependent manner. Similarly, curcumin derivatives markedly increased ROS production in colon cancer cells [44]. Furthermore, naringenin-inhibited cell growth was effectively increased through intercellular ROS production [45].…”

Section: Discussionmentioning

confidence: 97%

Naringenin Induces ROS-Mediated ER Stress, Autophagy, and Apoptosis in Human Osteosarcoma Cell Lines

et al. 2022

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Osteosarcoma, a primary bone tumor, responds poorly to chemotherapy and radiation therapy in children and young adults; hence, as the basis for an alternative treatment, this study investigated the cytotoxic and antiproliferative effects of naringenin on osteosarcoma cell lines, HOS and U2OS, by using cell counting kit-8 and colony formation assays. DNA fragmentation and the increase in the G2/M phase in HOS and U2OS cells upon treatment with various naringenin concentrations were determined by using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and Annexin V/propidium iodide double staining, respectively. Flow cytometry was performed, and 2′,7′-dichlorodihydrofluorescein diacetate, JC-1, and Fluo-4 AM ester probes were examined for reactive oxygen species (ROS) generation, mitochondrial membrane potential, and intracellular calcium levels, respectively. Caspase activation, cell cycle, cytosolic and mitochondrial, and autophagy-related proteins were determined using with western blotting. The results indicated that naringenin significantly inhibited the viability and proliferation of osteosarcoma cells in a dose-dependent manner. In addition, naringenin induced cell cycle arrest in osteosarcoma cells by inhibiting cyclin B1 and cyclin-dependent kinase 1 expression and upregulating p21 expression. Furthermore, naringenin significantly inhibited the growth of osteosarcoma cells by increasing the intracellular ROS level. Naringenin induced endoplasmic reticulum (ER) stress-mediated apoptosis through the upregulation of ER stress markers, GRP78 and GRP94. Naringenin caused acidic vesicular organelle formation and increased autophagolysosomes, microtubule-associated protein-light chain 3-II protein levels, and autophagy. The findings suggest that the induction of cell apoptosis, cell cycle arrest, and autophagy by naringenin through mitochondrial dysfunction, ROS production, and ER stress signaling pathways contribute to the antiproliferative effect of naringenin on osteosarcoma cells.

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The Novel Curcumin Derivative 1g Induces Mitochondrial and ER-Stress-Dependent Apoptosis in Colon Cancer Cells by Induction of ROS Production

Cited by 15 publications

References 49 publications

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

Proapoptotic Effect and Molecular Docking Analysis of Curcumin–Resveratrol Hybrids in Colorectal Cancer Chemoprevention

Naringenin Induces ROS-Mediated ER Stress, Autophagy, and Apoptosis in Human Osteosarcoma Cell Lines

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