Pyrrolo [3,4- b]-quinolin-9-amine compound FZU-0038-056 suppresses triple-negative breast cancer partially through inhibiting the expression of Bcl-2

Danping Wang; Zhi Nie; Xiaoyan Jiang; Jinxiang Ye; Zhimin Wei; Dating Cheng; Chenyang Wang; Yingying Wu; Rong Liu; Haijun Chen; Ceshi Chen; Chunyan Wang

doi:10.18632/aging.103232

Pyrrolo [3,4- b]-quinolin-9-amine compound FZU-0038-056 suppresses triple-negative breast cancer partially through inhibiting the expression of Bcl-2

Aging (Albany NY). 2020 May 23;12(10):9621-9632. doi: 10.18632/aging.103232. Epub 2020 May 23.

Authors

Danping Wang¹, Zhi Nie^{2

3

4}, Xiaoyan Jiang⁵, Jinxiang Ye⁶, Zhimin Wei⁷, Dating Cheng¹, Chenyang Wang¹, Yingying Wu^{1

3

4}, Rong Liu^{3

8}, Haijun Chen⁶, Ceshi Chen^{3

9

10}, Chunyan Wang¹

Affiliations

¹ Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China.
² Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan,, China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
⁴ Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming 650204, China.
⁵ Medical Faculty of Kunming University of Science and Technology, Kunming 650500, China.
⁶ College of Chemistry, Fuzhou University, Fuzhou 350116, Fujian, China.
⁷ Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
⁸ Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China.
⁹ KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
¹⁰ Institute of Translation Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.

Abstract

Triple-negative breast cancer (TNBC) has a poorer prognosis than other subtypes of breast cancer; however, it lacks effective targeted therapies clinically. In this study, we found FZU-0038-056, a novel compound derived from last-stage functionalization of tetrahydro-β-carboline scaffold, showed the most potent anti-cancer activity against TNBC cells among the 42 synthesized derivatives. We found FZU-0038-056 significantly induces apoptosis in HCC1806 and HCC1937 TNBC cells. FZU-0038-056 reduces the expression levels of several anti-apoptosis proteins, including Bcl-2, Mcl-1 and XIAP. Furthermore, we found FZU-0038-056 induces apoptosis partially through inhibiting the expression of Bcl-2. Finally, we found FZU-0038-056 significantly suppresses HCC1806 xenograft tumor growth in nude mice without affecting their body weight. Therefore, FZU-0038-056 has the potential to be a new anticancer agent for treating human TNBC.

Keywords: Bcl-2; apoptosis; tetrahydro-β-carboline derivatives; triple-negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemistry
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism
Carbolines / chemistry*
Cell Line, Tumor
Female
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Humans
Mice
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Pyrroles / chemistry
Quinolines / chemistry
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / genetics
X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

Amines
Antineoplastic Agents
Apoptosis Regulatory Proteins
Carbolines
Heterocyclic Compounds
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
Pyrroles
Quinolines
X-Linked Inhibitor of Apoptosis Protein
tryptoline