All-trans Retinoic Acid Enhances Anti-proliferative Effect of Dual PI3K and MTOR Inhibitor NVP-BEZ235 in Triple Negative Breast Cancer

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2025 Mar 5

PMID 40042556

Authors

Suranur Ayvaz

Zeynep Busra Bolat

Affiliations

Soon will be listed here.

Abstract

Breast cancer remains the most diagnosed cancer in females and one of its most challenging subtypes is Triple Negative Breast Cancer (TNBC). Treatment of TNBC presents challenges due to limited targeted therapies, inefficacy of chemotherapy, and severe side effects. Therefore, combination therapies are preferred to reduce toxicity and drug resistance. All-trans-retinoic acid (ATRA), a key player in cell growth, differentiation, and organogenesis, also exerts significant anti-cancer effects. NVP-BEZ235 is a dual PI3K and mTOR kinase inhibitor. In this study we investigated the anti-proliferative potential of NVP-BEZ235 and ATRA on TNBC cell line MDA-MB-231. The effective combination dosage was found to be 1 µM for NVP-BEZ235 and 5 µM for ATRA on MDA-MB-231 cells at 48 h. Combination treatment of NVP-BEZ235 and ATRA significantly reduced migration and colony formation compared to the control group. Co-treatment of NVP-BEZ235 and ATRA showed increase at G0/G1 phase in MDA-MB-231 cells. Treatment of NVP-BEZ235 and ATRA in MDA-MB-231 cells showed a significant increase in Caspase-3 genes, while a significant decrease in mTOR and BCL-2 genes were detected when compared to the untreated group. These results indicate that this combination therapy is a promising anti-cancer agent and has potential use in the treatment of TNBC.

References

Abdolahi M, Shokri F, Hosseini M, Shadanian M, Saboor-Yaraghi A . The combined effects of all-trans-retinoic acid and docosahexaenoic acid on the induction of apoptosis in human breast cancer MCF-7 cells. J Cancer Res Ther. 2016; 12(1):204-8. DOI: 10.4103/0973-1482.154071. View

Aouad P, Saikali M, Abdel-Samad R, Fostok S, El-Houjeiri L, Pisano C . Antitumor activities of the synthetic retinoid ST1926 in two-dimensional and three-dimensional human breast cancer models. Anticancer Drugs. 2017; 28(7):757-770. DOI: 10.1097/CAD.0000000000000511. View

Bao B, Prasad A . Targeting CSC in a Most Aggressive Subtype of Breast Cancer TNBC. Adv Exp Med Biol. 2019; 1152:311-334. DOI: 10.1007/978-3-030-20301-6_17. View

BOLLAG W, Holdener E . Retinoids in cancer prevention and therapy. Ann Oncol. 1992; 3(7):513-26. DOI: 10.1093/oxfordjournals.annonc.a058252. View

Bray F, Laversanne M, Sung H, Ferlay J, Siegel R, Soerjomataram I . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. DOI: 10.3322/caac.21834. View

Cai J, Xia J, Zou J, Wang Q, Ma Q, Sun R . The PI3K/mTOR dual inhibitor NVP-BEZ235 stimulates mutant p53 degradation to exert anti-tumor effects on triple-negative breast cancer cells. FEBS Open Bio. 2020; 10(4):535-545. PMC: 7137801. DOI: 10.1002/2211-5463.12806. View

Cetin F, Kosba S, Abdik H, Bolat Z . Synergistic anti-proliferative and apoptotic effect of NVP-BEZ235 and curcumin on human SH-SY5Y neuroblastoma cells. Med Oncol. 2023; 41(1):11. DOI: 10.1007/s12032-023-02239-8. View

Chavda V, Nalla L, Balar P, Bezbaruah R, Apostolopoulos V, Singla R . Advanced Phytochemical-Based Nanocarrier Systems for the Treatment of Breast Cancer. Cancers (Basel). 2023; 15(4). PMC: 9954440. DOI: 10.3390/cancers15041023. View

Chlapek P, Slavikova V, Mazanek P, Sterba J, Veselska R . Why Differentiation Therapy Sometimes Fails: Molecular Mechanisms of Resistance to Retinoids. Int J Mol Sci. 2018; 19(1). PMC: 5796081. DOI: 10.3390/ijms19010132. View

10.

Costa R, Han H, Gradishar W . Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018; 169(3):397-406. DOI: 10.1007/s10549-018-4697-y. View

11.

Donato L, Noy N . Suppression of mammary carcinoma growth by retinoic acid: proapoptotic genes are targets for retinoic acid receptor and cellular retinoic acid-binding protein II signaling. Cancer Res. 2005; 65(18):8193-9. DOI: 10.1158/0008-5472.CAN-05-1177. View

12.

Ellis H, Ma C . PI3K Inhibitors in Breast Cancer Therapy. Curr Oncol Rep. 2019; 21(12):110. DOI: 10.1007/s11912-019-0846-7. View

13.

Fazio N, Buzzoni R, Baudin E, Antonuzzo L, Hubner R, Lahner H . A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours. Anticancer Res. 2016; 36(2):713-9. PMC: 5076549. View

14.

Garrido-Castro A, Saura C, Barroso-Sousa R, Guo H, Ciruelos E, Bermejo B . Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer. Breast Cancer Res. 2020; 22(1):120. PMC: 7607628. DOI: 10.1186/s13058-020-01354-y. View

15.

Giuli M, Hanieh P, Giuliani E, Rinaldi F, Marianecci C, Screpanti I . Current Trends in ATRA Delivery for Cancer Therapy. Pharmaceutics. 2020; 12(8). PMC: 7465813. DOI: 10.3390/pharmaceutics12080707. View

16.

Gupta G, Collier A, Lee D, Hoefer R, Zheleva V, van Reesema L . Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies. Cancers (Basel). 2020; 12(9). PMC: 7565566. DOI: 10.3390/cancers12092392. View

17.

Hormi-Carver K, Feagins L, Spechler S, Souza R . All trans-retinoic acid induces apoptosis via p38 and caspase pathways in metaplastic Barrett's cells. Am J Physiol Gastrointest Liver Physiol. 2006; 292(1):G18-27. DOI: 10.1152/ajpgi.00237.2006. View

18.

Howe L . Rexinoids and breast cancer prevention. Clin Cancer Res. 2007; 13(20):5983-7. DOI: 10.1158/1078-0432.CCR-07-1065. View

19.

Huang M, Ye Y, Chen S, Chai J, Lu J, Zhoa L . Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988; 72(2):567-72. View

20.

Lin G, Zhu S, Wu Y, Song C, Wang W, Zhang Y . ω-3 free fatty acids and all-trans retinoic acid synergistically induce growth inhibition of three subtypes of breast cancer cell lines. Sci Rep. 2017; 7(1):2929. PMC: 5462805. DOI: 10.1038/s41598-017-03231-9. View