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His-tagged pro-apoptotic peptides: enhancing cell internalization and anticancer effect in vitro

Aldo O González-Cruz1, José Juan Pérez-Trujillo2, Isaías Balderas-Rentería1

  • 1Laboratorio de Farmacología Molecular y Modelos Biológicos, Facultad de Ciencias Químicas, Universidad Autonoma de Nuevo Leon (UANL), Av. Guerrero S/N, Colonia Treviño, CP 64570, Monterrey, Nuevo León, Mexico.

Apoptosis : an International Journal on Programmed Cell Death
|September 17, 2025
PubMed

Insights

His-tagged pro-apoptotic peptides, particularly KLAK-H, show promise for cancer treatment by enhancing cellular uptake and inducing apoptosis in EGFR-positive cancer cells, despite EGFR-targeted peptides not meeting expectations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Delivery

Background:

  • Epidermal growth factor receptor (EGFR) overexpression in solid tumors correlates with poor prognosis and treatment resistance.
  • Overcoming drug resistance in EGFR-positive cancers remains a significant clinical challenge.
  • Tumor-homing cell-penetrating peptides offer potential for targeted cancer therapy and improved drug delivery.

Purpose of the Study:

  • To evaluate the anticancer potential of EGFR-targeted pro-apoptotic peptides (NRPD-KLAK-H, NRPD-CTMP4-H) and compare them with free His-tagged peptides (NRPD-H, KLAK-H, CTMP4-H).
  • To investigate the role of His-tag modification in enhancing peptide internalization and overcoming drug resistance in EGFR-positive cancers.

Main Methods:

  • MTT assays were used to determine cell viability and inhibitory concentrations (IC50).
  • TUNEL assays were employed to assess apoptosis induction.
  • Immunofluorescence microscopy was utilized to visualize and quantify peptide internalization into cancer cells.

Main Results:

  • KLAK-H and NRPD-KLAK-H demonstrated significant anticancer effects, inhibiting A-549 cell growth with IC50 values of 33.3 µM and 40.9 µM, respectively.
  • Apoptosis was induced by KLAK-H and NRPD-KLAK-H, as indicated by TUNEL assays.
  • His-tag modification improved peptide internalization, with KLAK-H/NRPD-KLAK-H showing better uptake than CTMP4-H/NRPD-CTMP4-H.

Conclusions:

  • His-tagged pro-apoptotic peptides, especially KLAK-H, show promise as potential cancer therapeutics due to enhanced cellular uptake and apoptosis induction.
  • While EGFR-targeted peptides did not achieve the expected outcomes, His-tag modification is a viable strategy to improve the efficacy of pro-apoptotic peptides in cancer treatment.
Keywords:
Anticancer peptideCTMP4 peptideCancer therapyEGFRKLAK peptidePro-apoptotic peptide

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