Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2024 May 16

PMID 38751629

Authors

Prasad R Kopparapu

Christiane V Lohr

Martin C Pearce

Shanthakumar Tyavanagimatt

Harikrishna Nakshatri

Siva K Kolluri

Affiliations

Soon will be listed here.

Abstract

The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic. About 80% of cancer deaths are due to metastases, and yet targeted therapies for metastatic cancers are scarce. We discovered a small molecule, BFC1103, which changes the conformation of Bcl-2 to convert the antiapoptotic protein to a proapoptotic protein. BFC1103-induced apoptosis is dependent on the expression levels of Bcl-2, with higher levels causing more apoptosis. BFC1103 suppressed the growth of breast cancer lung metastasis. BFC1103 has the potential for further optimization and development for clinical testing in metastatic cancers that express Bcl-2. This study demonstrates a new approach to target Bcl-2 using a small molecule, BFC1103, to suppress metastatic disease.

References

Kolluri S, Bruey-Sedano N, Cao X, Lin B, Lin F, Han Y . Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol. 2003; 23(23):8651-67. PMC: 262666. DOI: 10.1128/MCB.23.23.8651-8667.2003. View

Ryan C, Davids M . BCL-2 Inhibitors, Present and Future. Cancer J. 2019; 25(6):401-409. DOI: 10.1097/PPO.0000000000000408. View

Kumar M, Gupta D, Singh G, Sharma S, Bhat M, Prashant C . Novel polymeric nanoparticles for intracellular delivery of peptide Cargos: antitumor efficacy of the BCL-2 conversion peptide NuBCP-9. Cancer Res. 2014; 74(12):3271-81. PMC: 4089982. DOI: 10.1158/0008-5472.CAN-13-2015. View

Ploumaki I, Triantafyllou E, Koumprentziotis I, Karampinos K, Drougkas K, Karavolias I . Bcl-2 pathway inhibition in solid tumors: a review of clinical trials. Clin Transl Oncol. 2023; 25(6):1554-1578. PMC: 10203027. DOI: 10.1007/s12094-022-03070-9. View

Villalobos-Ortiz M, Ryan J, Mashaka T, Opferman J, Letai A . BH3 profiling discriminates on-target small molecule BH3 mimetics from putative mimetics. Cell Death Differ. 2019; 27(3):999-1007. PMC: 7205860. DOI: 10.1038/s41418-019-0391-9. View

Elson D, Nguyen B, Bernales S, Chakravarty S, Jang H, Korjeff N . Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline. ACS Pharmacol Transl Sci. 2023; 6(7):1028-1042. PMC: 10353065. DOI: 10.1021/acsptsci.2c00253. View

Davids M, Letai A . ABT-199: taking dead aim at BCL-2. Cancer Cell. 2013; 23(2):139-41. PMC: 3693952. DOI: 10.1016/j.ccr.2013.01.018. View

Patel J, Appaiah H, Burnett R, Bhat-Nakshatri P, Wang G, Mehta R . Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22. Oncogene. 2010; 30(11):1290-301. DOI: 10.1038/onc.2010.510. View

Montero J, Haq R . Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics. Cancer Discov. 2022; 12(5):1217-1232. PMC: 9306285. DOI: 10.1158/2159-8290.CD-21-1334. View

10.

Phillips J, Lohr C, Nguyen B, Buermeyer A, Kolluri S . Loss of the aryl hydrocarbon receptor increases tumorigenesis in p53-deficient mice. Toxicol Appl Pharmacol. 2022; 454:116191. DOI: 10.1016/j.taap.2022.116191. View

11.

Elson D, Nguyen B, Korjeff N, Wilferd S, Puig-Sanvicens V, Jang H . Suppression of Ah Receptor (AhR) increases the aggressiveness of TNBC cells and 11-Cl-BBQ-activated AhR inhibits their growth. Biochem Pharmacol. 2023; 215:115706. DOI: 10.1016/j.bcp.2023.115706. View

12.

Hata A, Engelman J, Faber A . The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics. Cancer Discov. 2015; 5(5):475-87. PMC: 4727530. DOI: 10.1158/2159-8290.CD-15-0011. View

13.

Choi J, Choi K, Benveniste E, Rho S, Hong Y, Lee J . Bcl-2 promotes invasion and lung metastasis by inducing matrix metalloproteinase-2. Cancer Res. 2005; 65(13):5554-60. DOI: 10.1158/0008-5472.CAN-04-4570. View

14.

Kapoor S, Gupta D, Kumar M, Sharma S, Gupta A, Misro M . Intracellular delivery of peptide cargos using polyhydroxybutyrate based biodegradable nanoparticles: Studies on antitumor efficacy of BCL-2 converting peptide, NuBCP-9. Int J Pharm. 2016; 511(2):876-89. DOI: 10.1016/j.ijpharm.2016.07.077. View

15.

Li H, Kolluri S, Gu J, Dawson M, Cao X, Hobbs P . Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science. 2000; 289(5482):1159-64. DOI: 10.1126/science.289.5482.1159. View

16.

Kolluri S, Zhu X, Zhou X, Lin B, Chen Y, Sun K . A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell. 2008; 14(4):285-98. PMC: 2667967. DOI: 10.1016/j.ccr.2008.09.002. View

17.

Nguyen B, Stevens B, Elson D, Finlay D, Gamble J, Kopparapu P . 11-Cl-BBQ, a select modulator of AhR-regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27. FEBS J. 2022; 290(8):2064-2084. PMC: 10807707. DOI: 10.1111/febs.16683. View

18.

Morgan E, Gamble J, Pearce M, Elson D, Tanguay R, Kolluri S . Improved in vivo targeting of BCL-2 phenotypic conversion through hollow gold nanoshell delivery. Apoptosis. 2019; 24(5-6):529-537. PMC: 8918063. DOI: 10.1007/s10495-019-01531-1. View

19.

Montero J, Letai A . Why do BCL-2 inhibitors work and where should we use them in the clinic?. Cell Death Differ. 2017; 25(1):56-64. PMC: 5729538. DOI: 10.1038/cdd.2017.183. View

20.

Letai A . Hiding from ABT-737 in lymph nodes. Blood. 2009; 113(18):4132-3. DOI: 10.1182/blood-2008-12-192831. View