A small-molecule anti-cancer drug for long-acting lysosomal damage

Area of Science:

• Oncology
• Cell Biology
• Drug Development

Background:

• Lysosomes are crucial targets for cancer therapy and overcoming drug resistance.
• Current lysosome-targeting anticancer drugs face limitations due to short treatment times and low efficiency.
• Developing strategies for sustained lysosomal targeting is essential for improved cancer treatment.

Purpose of the Study:

• To develop a novel lysosome-targeting anticancer drug with long-term efficacy.
• To investigate the potential of an adhesive-bandage approach for sustained drug delivery to lysosomes.
• To evaluate the anticancer effects and drug resistance overcoming capabilities of the new drug.

Main Methods:

• Synthesis of a long-term lysosome-targeting anticancer drug (LLAD) incorporating a SLC38A9-targeting moiety and an alkaline component.
• Treatment of HeLa cells with LLAD to assess lysosomal alkalinization and drug retention over multiple cell passages.
• In vivo studies to compare the long-term anticancer effect of LLAD with cisplatin.

Main Results:

• LLAD rapidly alkalinized lysosomes and demonstrated sustained presence in lysosomes up to passage 15.
• LLAD induced apoptosis in HeLa cells via long-term lysosomal damage.
• LLAD exhibited a superior long-term anticancer effect in vivo compared to cisplatin.

Conclusions:

• The developed adhesive-bandage approach enables long-term lysosomal targeting and inhibition.
• LLAD shows significant potential as a therapeutic agent for cancer treatment and overcoming drug resistance.
• This study provides a promising candidate drug, LLAD, and a novel strategy for developing advanced lysosome-targeting anticancer therapies.