5-O-Acetyl-Renieramycin T from Blue Sponge Xestospongia sp. Induces Lung Cancer Stem Cell Apoptosis

Chantarawong, Wipa; Chamni, Supakarn; Suwanborirux, Khanit; Saito, Naoki; Chanvorachote, Pithi

doi:10.3390/md17020109

Cited by 35 publications

(34 citation statements)

References 58 publications

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“…Natural products and their derivatives contribute to approximately 63% of new drug development. 9 Many studies have shown that myricetin, a flavonoid widely found in tea, fruits, and herbs, has antiproliferative effects on various cancers. [10][11][12] Shih et al found that the invasion and migration ability of A549 cells could be suppressed by blocking the extracellular regulated protein kinases signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Anticancer effects of myricetin derivatives in non‐small cell lung cancer in vitro and in vivo

Zha

Chen

et al. 2021

Pharmacology Res & Perspec

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Lung cancer is the most common cause of cancer‐related deaths. Moreover, exploring efficient tumor‐killing drugs is urgently needed. In our study, several derivative compounds of myricetin were synthesized and tested. Experiments on non‐small cell lung cancer (NSCLC) showed that S4‐2‐2 (5,7‐dimethoxy‐3‐(4‐(methyl(1‐(naphthalen‐2‐ylsulfonyl)piperidin‐4‐yl)amino)butoxy)‐2‐(3,4,5‐trimethoxyphenyl)‐4H‐chromen‐4‐one) had the strongest effect on A549 cell inhibition across all compounds. Furthermore, S4‐2‐2‐treated A549 cells were also suppressed when transplanted into immunodeficient mice. Particularly, we found that the migration and invasiveness of A549 cells became suppressed upon treatment with S4‐2‐2. Furthermore, the compound significantly induced cell apoptosis, but did not affect the cell cycle of A549 cells. Finally, we revealed that S4‐2‐2 inhibited the biological function of NSCLC cells by regulating the protein process in the endoplasmic reticulum, and then by inducing the expression of apoptosis‐related proteins. Taken together, S4‐2‐2 was shown to act as a potential molecular inhibitor of A549 cells.

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Section: Introductionmentioning

confidence: 99%

Anticancer effects of myricetin derivatives in non‐small cell lung cancer in vitro and in vivo

Zha

Chen

et al. 2021

Pharmacology Res & Perspec

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“…Recently, its anti-cancer activities have been reported against several types of cancer cells, such as colon (HCT116), prostate (DU145) [46], non-small cell lung (H292, H460, and QG56) [47], breast (T47D), and pancreatic (AsPC1) cancer cells [45]. Moreover, a modified form of RT, 5-O-acetyl-renieramycin T, was shown to induce the death of lung cancer stem cells and sensitize cisplatin-mediated apoptosis in lung cancer cells [48]. Our previous study revealed that the effects of RT on the apoptotic mechanism depended on the disappearance of Mcl-1 through the increase in Mcl-1 protein degradation [23].…”

Section: Discussionmentioning

confidence: 99%

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Petsri

Yokoya

Tungsukruthai

et al. 2020

Cancers

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Myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins are promising targets for cancer therapy. Here, we investigated the structure–activity relationships (SARs) and performed molecular docking analysis of renieramycin T (RT) and its analogues and identified the critical functional groups of Mcl-1 targeting. RT have a potent anti-cancer activity against several lung cancer cells and drug-resistant primary cancer cells. RT mediated apoptosis through Mcl-1 suppression and it also reduced the level of Bcl-2 in primary cells. For SAR study, five analogues of RT were synthesized and tested for their anti-cancer and Mcl-1- and Bcl-2-targeting effects. Only two of them (TM-(–)-18 and TM-(–)-4a) exerted anti-cancer activities with the loss of Mcl-1 and partly reduced Bcl-2, while the other analogues had no such effects. Specific cyanide and benzene ring parts of RT’s structure were identified to be critical for its Mcl-1-targeting activity. Computational molecular docking indicated that RT, TM-(–)-18, and TM-(–)-4a bound to Mcl-1 with high affinity, whereas TM-(–)-45, a compound with a benzene ring but no cyanide for comparison, showed the lowest binding affinity. As Mcl-1 helps cancer cells evading apoptosis, these data encourage further development of RT compounds as well as the design of novel drugs for treating Mcl-1-driven cancers.

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“…Interestingly, RT, the renieramycin–ecteinascidin hybrids in the tetrahydroisoquinoline alkaloid family, showed strong cytotoxicity in several cancer cell lines including colon (HCT116), prostate (DU145), non-small cell lung (H292, H460 and QG56), breast (T47D), and pancreatic (AsPC1) cancers [39,53,54,55]. Moreover, our previous study suggested that 5- O -acetyl-renieramycin T, a modified compound of RT, exerted a potential to suppress cancer stem cell (CSCs) growth, which is represented by a decrease in the CSCs markers CD44 and CD133 due to depletion of the protein kinase B (AKT) signal resulting in apoptosis induction of CSCs [56]. However, cell death mechanisms in CSCs and cancer cells might be different since CSCs have special characteristics only found in the stem cell population such as metabolic activities, signaling pathways, and cell cycle regulation [57,58,59].…”

Section: Discussionmentioning

confidence: 99%

Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action

et al. 2019

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Among malignancies, lung cancer is the major cause of cancer death. Despite the advance in lung cancer therapy, the five-year survival rate is extremely restricted due to therapeutic failure and disease relapse. Targeted therapies selectively inhibiting certain molecules in cancer cells have been accepted as promising ways to control cancer. In lung cancer, evidence has suggested that the myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of the Bcl-2 family, is a target for drug action. Herein, we report the Mcl-1 targeting activity of renieramycin T (RT), a marine-derived tetrahydroisoquinoline alkaloid that was isolated from the Thai blue sponge Xestospongia sp. RT was shown to be dominantly toxic to lung cancer cells compared to the normal cells in the lung. The cytotoxicity of this compound toward lung cancer cells was mainly exerted through apoptosis induction. For the mechanism of action, we found that RT mediated activation of p53 protein and caspase-9 and -3 activations. While others Bcl-2 family proteins (Bcl-2, Bak, and Bax) were minimally changed in response to RT, Mcl-1 protein was dramatically diminished. We further performed the cycloheximide experiment and found that the half-life of Mcl-1 was significantly shortened by RT treatment. When MG132, a potent selective proteasome inhibitor, was utilized, it could restore the Mcl-1 level. Furthermore, immunoprecipitation analysis revealed that RT significantly increased the formation of Mcl-1-ubiquitin complex compared to the non-treated control. In conclusion, we report the potential apoptosis induction of RT with a mechanism of action involving the targeting of Mcl-1 for ubiquitin-proteasomal degradation. As Mcl-1 is critical for cancer cell survival and chemotherapeutic failure, this novel information regarding the Mcl-1-targeted compound would be beneficial for the development of efficient anti-cancer strategies or targeted therapies.

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5-O-Acetyl-Renieramycin T from Blue Sponge Xestospongia sp. Induces Lung Cancer Stem Cell Apoptosis

Cited by 35 publications

References 58 publications

Anticancer effects of myricetin derivatives in non‐small cell lung cancer in vitro and in vivo

Anticancer effects of myricetin derivatives in non‐small cell lung cancer in vitro and in vivo

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action

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