Thymoquinone and Costunolide Induce Apoptosis of Both Proliferative and Doxorubicin-Induced-Senescent Colon and Breast Cancer Cells

Overview

Journal Integr Cancer Ther

Publisher Sage Publications

Specialties Oncology
Pharmacology

Date 2021 Sep 7

PMID 34490824

Citations 14

Authors

Ali H El-Far

Kavitha Godugu

Ahmed E Noreldin

Amna A Saddiq

Omar A Almaghrabi

Soad K Al Jaouni

Shaker A Mousa

Affiliations

Soon will be listed here.

Abstract

Doxorubicin (Dox) induces senescence in numerous cancer cell types, but these senescent cancer cells relapse again if they are not eliminated. On this principle, we investigated the apoptotic effect of thymoquinone (TQ), the active ingredient of seeds and costunolide (COS), the active ingredient of , on the senescent colon (Sen-HCT116) and senescent breast (Sen-MCF7) cancer cell lines in reference to their corresponding proliferative cells to rapidly eliminate the senescent cancer cells. The senescence markers of Sen-HCT116 and Sen-MCF7 were determined by a significant decrease in bromodeoxyuridine (BrdU) incorporation and significant increases in SA-β-gal, p53, and p21 levels. Then proliferative, Sen-HCT116, and Sen-MCF7 cells were subjected to either TQ (50 µM) or COS (30 µM), the Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), caspase 3 mRNA expression and its activity were established. Results revealed that TQ significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ, MCF7 + TQ, and MCF7 + Dox5 + TQ compared with their corresponding controls. COS significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ and MCF7 + Dox5 + TQ compared with their related controls. Also, TQ and COS were significantly increased caspase 3 activity and cell proliferation of Sen-HCT116 and Sen-MCF7. The data revealed a higher sensitivity of senescent cells to TQ or COS than their corresponding proliferative cells.

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References

Glass A, Hoover R . Rising incidence of breast cancer: relationship to stage and receptor status. J Natl Cancer Inst. 1990; 82(8):693-6. DOI: 10.1093/jnci/82.8.693. View

El-Far A, Darwish N, Mousa S . Senescent Colon and Breast Cancer Cells Induced by Doxorubicin Exhibit Enhanced Sensitivity to Curcumin, Caffeine, and Thymoquinone. Integr Cancer Ther. 2020; 19:1534735419901160. PMC: 7025418. DOI: 10.1177/1534735419901160. View

Di X, Shiu R, Newsham I, Gewirtz D . Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to adriamycin. Biochem Pharmacol. 2009; 77(7):1139-50. DOI: 10.1016/j.bcp.2008.12.016. View

Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown J . Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998; 282(5393):1497-501. DOI: 10.1126/science.282.5393.1497. View

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

Wang C, Youle R . The role of mitochondria in apoptosis*. Annu Rev Genet. 2009; 43:95-118. PMC: 4762029. DOI: 10.1146/annurev-genet-102108-134850. View

Milczarek M . The Premature Senescence in Breast Cancer Treatment Strategy. Cancers (Basel). 2020; 12(7). PMC: 7408867. DOI: 10.3390/cancers12071815. View

Shao A, Sun H, Geng Y, Peng Q, Wang P, Chen J . Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence. Cell Death Differ. 2016; 23(5):865-75. PMC: 4832105. DOI: 10.1038/cdd.2015.150. View

Frohlich T, Ndreshkjana B, Muenzner J, Reiter C, Hofmeister E, Mederer S . Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer. ChemMedChem. 2016; 12(3):226-234. DOI: 10.1002/cmdc.201600594. View

10.

Drummond C, Finlay G, Broome L, Marshall E, Richardson E, Baguley B . Action of SN 28049, a new DNA binding topoisomerase II-directed antitumour drug: comparison with doxorubicin and etoposide. Invest New Drugs. 2010; 29(5):1102-10. DOI: 10.1007/s10637-010-9473-8. View

11.

Kim Y, Choi H, Nam G, Choi B . Costunolide promotes the proliferation of human hair follicle dermal papilla cells and induces hair growth in C57BL/6 mice. J Cosmet Dermatol. 2018; 18(1):414-421. PMC: 7379667. DOI: 10.1111/jocd.12674. View

12.

Debacq-Chainiaux F, Erusalimsky J, Campisi J, Toussaint O . Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009; 4(12):1798-806. DOI: 10.1038/nprot.2009.191. View

13.

Tong Y, Zhao W, Zhou C, Wawrowsky K, Melmed S . PTTG1 attenuates drug-induced cellular senescence. PLoS One. 2011; 6(8):e23754. PMC: 3157437. DOI: 10.1371/journal.pone.0023754. View

14.

Qian Y, Chen X . Senescence regulation by the p53 protein family. Methods Mol Biol. 2013; 965:37-61. PMC: 3784259. DOI: 10.1007/978-1-62703-239-1_3. View

15.

Johnstone R, Ruefli A, Lowe S . Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002; 108(2):153-64. DOI: 10.1016/s0092-8674(02)00625-6. View

16.

Gali-Muhtasib H, Diab-Assaf M, Boltze C, Al-Hmaira J, Hartig R, Roessner A . Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol. 2004; 25(4):857-66. View

17.

Atta M, Almadaly E, El-Far A, Saleh R, Assar D, Al Jaouni S . Thymoquinone Defeats Diabetes-Induced Testicular Damage in Rats Targeting Antioxidant, Inflammatory and Aromatase Expression. Int J Mol Sci. 2017; 18(5). PMC: 5454832. DOI: 10.3390/ijms18050919. View

18.

Tacar O, Sriamornsak P, Dass C . Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol. 2013; 65(2):157-70. DOI: 10.1111/j.2042-7158.2012.01567.x. View

19.

Roepke M, Diestel A, Bajbouj K, Walluscheck D, Schonfeld P, Roessner A . Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther. 2007; 6(2):160-9. DOI: 10.4161/cbt.6.2.3575. View

20.

Jackson J, Pereira-Smith O . Primary and compensatory roles for RB family members at cell cycle gene promoters that are deacetylated and downregulated in doxorubicin-induced senescence of breast cancer cells. Mol Cell Biol. 2006; 26(7):2501-10. PMC: 1430319. DOI: 10.1128/MCB.26.7.2501-2510.2006. View