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Novel benzo[a]phenoxazine derivatives C9, A36, and A42 show promise as targeted cancer therapies. These compounds selectively induce cancer cell death by disrupting lysosomes, offering a new approach for breast and colorectal cancer treatment.

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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.