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ADPB Sensitivity in Breast Cancer is Correlated with LAT1 Expression: An in vitro Study of a Novel Theranostic
Kharisma Perdani Kusumahstuti1,2,3, Holis Abdul Holik4, Muhammad Hasan Bashari5
1Doctoral Study Program, Faculty of Medicine, Universitas Padjadjaran, Bandung, Jawa Barat, Indonesia.
Introduction:
The most common cancer in women worldwide is breast cancer. Current systemic chemotherapies do not target specific cells, which makes them toxic to normal cells. The L-type amino acid transporter 1 (LAT1) is overexpressed in a lot of cancers, also in breast cancer. Few ligand such as JPH203 (KYT-0353), a known tyrosine analogue that specifically blocks LAT1, but have limitation. It has led to efforts to create next-generation LAT1 inhibitors or prodrugs with better qualities for target therapy or diagnostic.
Purpose:
We investigated a new agent (S)-2-amino-4-(3,5-dichlorophenyl) butanoic acid (ADPB) as a new LAT1 inhibitor in three breast cancer cell lines: MCF-7 luminal A, HCC1954 HER2+, and MDA-MB-231 triple-negative. We hypothesized that the levels of LAT1 expression would influence the efficacy of ADPB. This could lead to a treatment that is more targeted and less harmful.
Methods:
We used RT-qPCR to determine the LAT1 mRNA expression in each cell line and MTT for find IC50 values. These cells were given ADPB (0-160 µM) for 72 hours. There were three replication tests.
Results:
ADPB diminished the viability of cells in all cell lines, and the effect was dose-dependent. MDA-MB-231 was the most sensitive cell line (IC5 0 = 118,1 µM 95% Cl (118,25-118,48), HCC-1954 was the middle-sensitive cell line (IC5 0 = 126,2 µM 95% Cl (126,11-126,68), and MCF-7 was the least sensitive cell line (IC5 0 = 127,3 µM 95% Cl (127,9-131,23). Study found an inverse relationship between LAT1 expression and IC5 0 in all cell lines, with higher LAT1 levels correlated with lower IC5 0.
Conclusion:
In this exploratory in vitro study, ADPB predominantly induces cytostatic effects, with cellular sensitivity associated with LAT1 expression in breast cancer cell line.
Insights
A novel agent, (S)-2-amino-4-(3,5-dichlorophenyl) butanoic acid (ADPB), shows potential as a targeted breast cancer therapy by inhibiting L-type amino acid transporter 1 (LAT1). Its efficacy correlates with LAT1 expression levels in cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer is the most common cancer in women globally.
- Current chemotherapies lack specificity, leading to toxicity in normal cells.
- L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers, including breast cancer, making it a potential therapeutic target.
Purpose of the Study:
- To investigate the efficacy of a new LAT1 inhibitor, (S)-2-amino-4-(3,5-dichlorophenyl) butanoic acid (ADPB), in three distinct breast cancer cell lines.
- To determine if LAT1 expression levels influence ADPB's effectiveness in inhibiting cancer cell viability.
- To explore ADPB as a potential targeted therapy with reduced harm to normal cells.
Main Methods:
- Utilized RT-qPCR to quantify LAT1 mRNA expression across MCF-7, HCC1954, and MDA-MB-231 breast cancer cell lines.
- Determined IC50 values using MTT assays after exposing cells to varying concentrations of ADPB (0-160 µM) for 72 hours.
- Conducted three independent replication tests to ensure the reliability of the results.
Main Results:
- ADPB demonstrated a dose-dependent reduction in cancer cell viability across all tested cell lines.
- MDA-MB-231 (triple-negative) cells were most sensitive to ADPB (IC50 = 118.1 µM), followed by HCC-1954 (HER2+) (IC50 = 126.2 µM), and MCF-7 (luminal A) (IC50 = 127.3 µM).
- An inverse correlation was observed between LAT1 expression levels and IC50 values, indicating higher LAT1 expression leads to greater sensitivity to ADPB.
Conclusions:
- ADPB exhibits predominantly cytostatic effects in breast cancer cell lines.
- Cellular sensitivity to ADPB is significantly associated with LAT1 expression levels.
- ADPB represents a promising agent for targeted therapy in LAT1-expressing breast cancers.
