Computational and in vitro analyses on synergistic effects of paclitaxel and thymoquinone in suppressing invasive breast cancer cells.
Apoptosis
Autophagy
Breast neoplasm
Paclitaxel
Thymoquinone
Journal
Molecular biology reports
ISSN: 1573-4978
Titre abrégé: Mol Biol Rep
Pays: Netherlands
ID NLM: 0403234
Informations de publication
Date de publication:
06 Mar 2024
06 Mar 2024
Historique:
received:
03
01
2024
accepted:
07
02
2024
medline:
6
3
2024
pubmed:
6
3
2024
entrez:
6
3
2024
Statut:
epublish
Résumé
In the present experiment, we evaluated the impact of thymoquinone (TQ) and paclitaxel (PTX) treatment on MDA-MB-231 cell line growth inhibition via controlling apoptosis/autophagy. MDA-MB-231cells were exposed to PTX (0, 25, 50, 75, and 100 nM), TQ (0, 25, 50, 75, and 100 µM), and combinations for 48 h. After the MTT assessment, dose-response curves and IC50 values were calculated, and the combination synergism was evaluated using the Compusyn software. Following the treatment with PTX, TQ, and combinations at IC50 doses, the expression of apoptosis and autophagy genes was assessed in cells. The GraphPad Prism program was used to analyze the data, and Tukey's test at p < 0.05 was then run. PTX, TQ, and their combinations inhibited MDA-MB-231cell proliferation and viability dose-dependently. TQ reduced the effective concentration (IC50) of PTX in co-treatment groups. PTX and TQ showed antagonistic effects when cell proliferation declined above 70%. Antagonistic effects shifted into additive and synergistic effects upon increasing PTX concentration, indicated by diminished cell proliferation below 70%. PTX-TQ co-treatment significantly enhanced P53 and BAX expression while reducing Bcl-2 expression. Also, their combination increased Beclin-1, ATG-5, and ATG-7 expression in treated cells. Effective concentrations of TQ and PTX had synergic effects and inhibited breast cancer cells via prompting apoptosis and autophagy in vitro.
Sections du résumé
BACKGROUND
BACKGROUND
In the present experiment, we evaluated the impact of thymoquinone (TQ) and paclitaxel (PTX) treatment on MDA-MB-231 cell line growth inhibition via controlling apoptosis/autophagy.
MATERIALS AND RESULTS
RESULTS
MDA-MB-231cells were exposed to PTX (0, 25, 50, 75, and 100 nM), TQ (0, 25, 50, 75, and 100 µM), and combinations for 48 h. After the MTT assessment, dose-response curves and IC50 values were calculated, and the combination synergism was evaluated using the Compusyn software. Following the treatment with PTX, TQ, and combinations at IC50 doses, the expression of apoptosis and autophagy genes was assessed in cells. The GraphPad Prism program was used to analyze the data, and Tukey's test at p < 0.05 was then run. PTX, TQ, and their combinations inhibited MDA-MB-231cell proliferation and viability dose-dependently. TQ reduced the effective concentration (IC50) of PTX in co-treatment groups. PTX and TQ showed antagonistic effects when cell proliferation declined above 70%. Antagonistic effects shifted into additive and synergistic effects upon increasing PTX concentration, indicated by diminished cell proliferation below 70%. PTX-TQ co-treatment significantly enhanced P53 and BAX expression while reducing Bcl-2 expression. Also, their combination increased Beclin-1, ATG-5, and ATG-7 expression in treated cells.
CONCLUSION
CONCLUSIONS
Effective concentrations of TQ and PTX had synergic effects and inhibited breast cancer cells via prompting apoptosis and autophagy in vitro.
Identifiants
pubmed: 38446390
doi: 10.1007/s11033-024-09328-5
pii: 10.1007/s11033-024-09328-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
388Subventions
Organisme : Kermanshah University of Medical Sciences
ID : 4020374
Organisme : Kermanshah University of Medical Sciences
ID : 4020374
Organisme : Kermanshah University of Medical Sciences
ID : 4020374
Organisme : Kermanshah University of Medical Sciences
ID : 4020374
Organisme : Kermanshah University of Medical Sciences
ID : 4020374
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature B.V.
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660
doi: 10.3322/caac.21660
Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, Vignat J, Gralow JR, Cardoso F, Siesling S (2022) Current and future burden of breast cancer: global statistics for 2020 and 2040. Breast 66:15–23. https://doi.org/10.1016/j.breast.2022.08.010
doi: 10.1016/j.breast.2022.08.010
pubmed: 36084384
pmcid: 9465273
Gupta GK, Collier AL, Lee D, Hoefer RA, Zheleva V, van Siewertsz LL, Tang-Tan AM, Guye ML, Chang DZ, Winston JS, Samli B, Jansen RJ, Petricoin EF, Goetz MP, Bear HD, Tang AH (2020) Perspectives on triple-negative breast Cancer: current treatment strategies, unmet needs, and potential targets for future therapies. Cancers 12(9):2392. https://doi.org/10.3390/cancers12092392
doi: 10.3390/cancers12092392
pubmed: 32846967
pmcid: 7565566
Bozorgi A, Bozorgi M, Khazaei M (2022) Immunotherapy and immunoengineering for breast cancer; a comprehensive insight into CAR-T cell therapy advancements, challenges and prospects. Cell Oncol 45(5):755–777. https://doi.org/10.1007/s13402-022-00700-w
doi: 10.1007/s13402-022-00700-w
Abu Samaan TM, Samec M, Liskova A, Kubatka P, Büsselberg D (2019) Paclitaxel’s mechanistic and clinical effects on breast Cancer. Biomolecules 9(12):789. https://doi.org/10.3390/biom9120789
doi: 10.3390/biom9120789
pubmed: 31783552
pmcid: 6995578
Zhu L, Chen L (2019) Progress in research on paclitaxel and tumor immunotherapy. Cell Mol Biol Lett 24(1):40. https://doi.org/10.1186/s11658-019-0164-y
doi: 10.1186/s11658-019-0164-y
pubmed: 31223315
pmcid: 6567594
Bernabeu E, Cagel M, Lagomarsino E, Moretton M, Chiappetta DA (2017) Paclitaxel: what has been done and the challenges remain ahead. Inte J Pharm 526(1):474–495. https://doi.org/10.1016/j.ijpharm.2017.05.016
doi: 10.1016/j.ijpharm.2017.05.016
Maloney SM, Hoover CA, Morejon-Lasso LV, Prosperi JR (2020) Mechanisms of Taxane Resistance. Cancers 12(11):3323. https://doi.org/10.3390/cancers12113323
doi: 10.3390/cancers12113323
pubmed: 33182737
pmcid: 7697134
Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, Yeger H (2017) Combination therapy in combating cancer. Oncotarget 8(23):38022–38043. https://doi.org/10.18632/oncotarget.16723
doi: 10.18632/oncotarget.16723
pubmed: 28410237
Almajali B, Al-Jamal HAN, Taib WRW, Ismail I, Johan MF, Doolaanea AA, Ibrahim WN (2021) Thymoquinone, as a Novel Therapeutic candidate of cancers. Pharmaceuticals 14(4):369. https://doi.org/10.3390/ph14040369
doi: 10.3390/ph14040369
pubmed: 33923474
pmcid: 8074212
Bozorgi A, Khazaei S, Khademi A, Khazaei M (2020) Natural and herbal compounds targeting breast cancer, a review based on cancer stem cells. Iran J Basic Med Sci 23(8):970–983. https://doi.org/10.22038/ijbms.2020.43745.10270
doi: 10.22038/ijbms.2020.43745.10270
pubmed: 32952942
pmcid: 7478260
Saghatelyan T, Tananyan A, Janoyan N, Tadevosyan A, Petrosyan H, Hovhannisyan A, Hayrapetyan L, Arustamyan M, Arnhold J, Rotmann A-R (2020) Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: a comparative, randomized, double-blind, placebo-controlled clinical trial. Phytomedicine 70:153218. https://doi.org/10.1016/j.phymed.2020.153218
doi: 10.1016/j.phymed.2020.153218
pubmed: 32335356
Chou J, Chou T (1991) Quantitation of synergism and antagonism of two or more drugs by computerized analysis. Synergism Antagonism Chemother: 223–244
Iannelli F, Roca MS, Lombardi R, Ciardiello C, Grumetti L, De Rienzo S, Moccia T, Vitagliano C, Sorice A, Costantini S, Milone MR, Pucci B, Leone A, Di Gennaro E, Mancini R, Ciliberto G, Bruzzese F, Budillon A (2020) Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition. J Exp Clin Cancer Res 39(1):213. https://doi.org/10.1186/s13046-020-01723-7
doi: 10.1186/s13046-020-01723-7
pubmed: 33032653
pmcid: 7545949
Harbeck N, Gnant M (2017) Breast cancer. Lancet 389(10074):1134–1150. https://doi.org/10.1016/s0140-6736(16)31891-8
doi: 10.1016/s0140-6736(16)31891-8
pubmed: 27865536
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2023) Efficacy and Safety of Trastuzumab as a single Agent in First-Line treatment of HER2-Overexpressing metastatic breast Cancer. J Clin Oncol 41(9):1638–1645. https://doi.org/10.1200/jco.22.02516
doi: 10.1200/jco.22.02516
pubmed: 36921335
Koh SJ, Ohsumi S, Takahashi M, Fukuma E, Jung KH, Ishida T, Dai MS, Chang CH, Dalvi T, Walker G, Bennett J, O’Shaughnessy J, Balmaña J (2022) Correction to: prevalence of mutations in BRCA and homologous recombination repair genes and real-world standard of care of Asian patients with HER2-negative metastatic breast cancer starting first-line systemic cytotoxic chemotherapy: subgroup analysis of the global BREAKOUT study. Breast Cancer 29(1):189–190. https://doi.org/10.1007/s12282-021-01299-w
doi: 10.1007/s12282-021-01299-w
pubmed: 34562259
Petrovic N, Sami A, Martinovic J, Zaric M, Nakashidze I, Lukic S, Jovanovic-Cupic S (2017) TIMP-3 mRNA expression levels positively correlates with levels of miR-21 in in situ BC and negatively in PR positive invasive BC. Pathol Res Pract 213(10):1264–1270. https://doi.org/10.1016/j.prp.2017.08.012
doi: 10.1016/j.prp.2017.08.012
pubmed: 28935174
Drucker AM, Morra DE, Prieto-Merino D, Ellis AG, Yiu ZZN, Rochwerg B, Di Giorgio S, Arents BWM, Burton T, Spuls PI, Schmitt J, Flohr C (2022) Systemic immunomodulatory treatments for atopic dermatitis: update of a Living Systematic Review and Network Meta-Analysis. JAMA Dermatol 158(5):523–532. https://doi.org/10.1001/jamadermatol.2022.0455
doi: 10.1001/jamadermatol.2022.0455
pubmed: 35293977
pmcid: 8928094
Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J (2023) Bevacizumab in Combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal Cancer: a Randomized Phase III Study. J Clin Oncol 41(21):3663–3669. https://doi.org/10.1200/jco.22.02760
doi: 10.1200/jco.22.02760
pubmed: 37459755
Ferraro MG, Piccolo M, Misso G, Santamaria R, Irace C (2022) Bioactivity and Development of Small Non-platinum Metal-based chemotherapeutics. Pharmaceutics 14(5):954. https://doi.org/10.3390/pharmaceutics14050954
doi: 10.3390/pharmaceutics14050954
pubmed: 35631543
pmcid: 9147010
Li G, Xu D, Sun J, Zhao S, Zheng D (2020) Paclitaxel inhibits proliferation and invasion and promotes apoptosis of breast cancer cells by blocking activation of the PI3K/AKT signaling pathway. Adv Clin Exp Med 29(11):1337–1345. https://doi.org/10.17219/acem/127681
doi: 10.17219/acem/127681
pubmed: 33269821
Talib WH (2017) Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone. Sci Pharm 85(3):27. https://doi.org/10.3390/scipharm85030027
doi: 10.3390/scipharm85030027
pubmed: 28671634
pmcid: 5620515
Woo CC, Hsu A, Kumar AP, Sethi G, Tan KHB (2013) Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: the role of p38 MAPK and ROS. PLoS ONE 8(10):e75356. https://doi.org/10.1371/journal.pone.0075356
doi: 10.1371/journal.pone.0075356
pubmed: 24098377
pmcid: 3788809
Alkhatib MH, Bawadud RS, Gashlan HM (2020) Incorporation of docetaxel and thymoquinone in borage nanoemulsion potentiates their antineoplastic activity in breast cancer cells. Sci Rep 10(1):18124. https://doi.org/10.1038/s41598-020-75017-5
doi: 10.1038/s41598-020-75017-5
pubmed: 33093596
pmcid: 7582846
Zhao S, Tang Y, Wang R, Najafi M (2022) Mechanisms of cancer cell death induction by paclitaxel: an updated review. Apoptosis 27(9):647–667. https://doi.org/10.1007/s10495-022-01750-z
doi: 10.1007/s10495-022-01750-z
pubmed: 35849264
Khing TM, Choi WS, Kim DM, Po WW, Thein W, Shin CY, Sohn UD (2021) The effect of paclitaxel on apoptosis, autophagy and mitotic catastrophe in AGS cells. Sci Rep 11(1):23490. https://doi.org/10.1038/s41598-021-02503-9
doi: 10.1038/s41598-021-02503-9
pubmed: 34873207
pmcid: 8648765
Aborehab NM, Elnagar MR, Waly NE (2021) Gallic acid potentiates the apoptotic effect of paclitaxel and carboplatin via overexpression of Bax and P53 on the MCF-7 human breast cancer cell line. J Biochem Mol Toxicol 35(2):e22638. https://doi.org/10.1002/jbt.22638
doi: 10.1002/jbt.22638
pubmed: 33002289
Bhattacharjee M, Upadhyay P, Sarker S, Basu A, Das S, Ghosh A, Ghosh S, Adhikary A (2020) Combinatorial therapy of Thymoquinone and Emodin synergistically enhances apoptosis, attenuates cell migration and reduces stemness efficiently in breast cancer. Biochim Biophys Acta Gen Subj 1864(11):129695. https://doi.org/10.1016/j.bbagen.2020.129695
doi: 10.1016/j.bbagen.2020.129695
pubmed: 32735937
Soni P, Kaur J, Tikoo K (2015) Dual drug-loaded paclitaxel–thymoquinone nanoparticles for effective breast cancer therapy. J Nanoparticle Res 17(1):18. https://doi.org/10.1007/s11051-014-2821-4
doi: 10.1007/s11051-014-2821-4
Şakalar Ç, İzgi K, İskender B, Sezen S, Aksu H, Çakır M, Kurt B, Turan A, Canatan H (2016) The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer. Tumor Biol 37(4):4467–4477. https://doi.org/10.1007/s13277-015-4307-0
doi: 10.1007/s13277-015-4307-0
Li W, He P, Huang Y, Li Y-F, Lu J, Li M, Kurihara H, Luo Z, Meng T, Onishi M (2021) Selective autophagy of intracellular organelles: recent research advances. Theranostics 11(1):222–256. https://doi.org/10.7150/thno.49860
doi: 10.7150/thno.49860
pubmed: 33391472
pmcid: 7681076
Boyer-Guittaut M, Poillet L, Liang Q, Bôle-Richard E, Ouyang X, Benavides GA, Chakrama F-Z, Fraichard A, Darley-Usmar VM, Despouy G (2014) The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells. Autophagy 10(6):986–1003. https://doi.org/10.4161/auto.28390
doi: 10.4161/auto.28390
pubmed: 24879149
pmcid: 4091181
Patergnani S, Missiroli S, Morciano G, Perrone M, Mantovani CM, Anania G, Fiorica F, Pinton P, Giorgi C (2021) Understanding the role of Autophagy in Cancer formation and progression is a real opportunity to treat and cure human cancers. Cancers 13(22). https://doi.org/10.3390/cancers13225622
Xu K, Zhu W, Xu A, Xiong Z, Zou D, Zhao H, Jiao D, Qing Y, Jamal MA, Wei HJ, Zhao HY (2022) Inhibition of FOXO1–mediated autophagy promotes paclitaxel–induced apoptosis of MDA–MB–231 cells. Mol Med Rep 25(2). https://doi.org/10.3892/mmr.2022.12588
Park J-H, Park S-A, Lee Y-J, Park H-W, Oh S-M (2020) PBK attenuates paclitaxel-induced autophagic cell death by suppressing p53 in H460 non-small-cell lung cancer cells. FEBS Open Bio 10(5):937–950. https://doi.org/10.1002/2211-5463.12855
doi: 10.1002/2211-5463.12855
pubmed: 32237067
pmcid: 7193173
Ünal TD, Hamurcu Z, Delibaşı N, Çınar V, Güler A, Gökçe S, Nurdinov N, Ozpolat B (2021) Thymoquinone inhibits proliferation and migration of MDA-MB-231 triple negative breast cancer cells by suppressing autophagy, Beclin-1 and LC3. Anticancer Agents Med Chem. 2021;21(3):355–364. https://doi.org/10.2174/1871520620666200807221047
Zhang Y, Fan Y, Huang S, Wang G, Han R, Lei F, Luo A, Jing X, Zhao L, Gu S (2018) Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway. Cancer Sci 109(12):3865–3873. https://doi.org/10.1111/cas.13808
doi: 10.1111/cas.13808
pubmed: 30259603
pmcid: 6272120