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Self-Assembling Imidazolium Nanoaggregates Trigger a Unique Dynamin-Dependent Cell Death via Cytoplasmic

Sayari Dewan1, Himanshu Sonker1, Kajal Chaudhary1

  • 1Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India.

Journal of Medicinal Chemistry
|May 23, 2025
PubMed

Insights

Researchers explored novel cell death pathways for apoptosis-resistant cancers. They developed delocalized lipophilic cation (DLC) nanoaggregates that induce nonapoptotic cell death, showing potential for cancer therapy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Nanomedicine

Background:

  • Apoptosis-resistant cancers pose a significant therapeutic challenge.
  • Identifying alternative cell death mechanisms is crucial for novel cancer treatments.

Purpose of the Study:

  • To investigate cell death induced by delocalized lipophilic cation (DLC) nanoaggregates in lung carcinoma cells.
  • To design and synthesize novel mitochondrion-targeting molecules for cancer therapy.

Main Methods:

  • Utilized dynamin-dependent pathways for cell death induction.
  • Synthesized fluorescent mitochondrion-toxic molecules.
  • Assessed cytotoxicity, nanoaggregate formation, metastasis inhibition, and mitochondrial function disruption.

Main Results:

  • DLCs induced a nonapoptotic cell death pathway with cytoplasmic vesicle accumulation and mitochondrial dysfunction.
  • The lead compound, L3, formed nanoaggregates and exhibited potent cytotoxicity against multiple cancer cell lines.
  • L3 inhibited metastasis, clonal expansion, and disrupted mitochondrial ATP levels, leading to MPTP opening and oxidative imbalance.

Conclusions:

  • L3 demonstrated significant antitumor activity both in vitro and in vivo.
  • The developed mitochondrion-toxic molecules show high potential for treating apoptosis-resistant cancers.

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