Anticancer Activity of Benzo[a]phenoxazine Compounds Promoting Lysosomal Dysfunction

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Specific cancer therapies, particularly for breast and colorectal cancers, remain a significant clinical challenge due to limited effective agents.
• Lysosomes are crucial for cancer cell survival, making them an attractive therapeutic target.
• Benzo[a]phenoxazine derivatives have demonstrated potent pharmacological activities.

Purpose of the Study:

• To investigate the anticancer activity of three novel benzo[a]phenoxazine derivatives (C9, A36, A42) against colorectal and breast cancer cell lines.
• To compare the efficacy of these compounds on cancer cells versus non-neoplastic cells.
• To elucidate the mechanism of action, focusing on lysosomal targeting and induction of lysosomal membrane permeabilization (LMP).

Main Methods:

• Testing of benzo[a]phenoxazine derivatives C9, A36, and A42 on RKO (colorectal) and MCF7 (breast) cancer cell lines, alongside non-neoplastic cell lines.
• Assessment of cell proliferation, survival, and migration.
• Analysis of lysosomal accumulation, lysosomal membrane permeabilization (LMP), intracellular pH, and reactive oxygen species (ROS) levels.

Main Results:

• The compounds C9, A36, and A42 exhibited selectivity towards cancer cells.
• These derivatives significantly reduced cancer cell proliferation, survival, and migration.
• Compounds accumulated in lysosomes, induced LMP, increased intracellular pH, and elevated ROS levels, leading to cancer cell death.

Conclusions:

• The investigated benzo[a]phenoxazine derivatives selectively target lysosomes in cancer cells.
• These compounds act as potent inducers of lysosomal membrane permeabilization (LMP).
• C9, A36, and A42 are promising candidates for developing novel LMP-inducing cancer therapies for breast and colorectal cancers.