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DNA damage triggers an interplay between wtp53 and c-Myc affecting lymphoma cell proliferation and Kaposi sarcoma

Andrea Arena1, Maria Saveria Gilardini Montani1, Maria Anele Romeo1

  • 1Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.

Biochimica Et Biophysica Acta. Molecular Cell Research
|November 3, 2021
PubMed

Insights

Combining PARP and CHK1 inhibitors shows promise for treating aggressive B cell lymphoma by disrupting DNA repair and reducing cell proliferation. This approach also impacts viral replication within cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Virology

Background:

  • DNA damage and repair interference is a key cancer treatment strategy.
  • Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma resistant to conventional therapies.

Purpose of the Study:

  • To investigate the efficacy of combining PARP-1/2/3 inhibitor AZD2461 with CHK1 inhibitor UCN-01 in PEL cells.
  • To elucidate the molecular mechanisms underlying the combination therapy's effects on cancer cells and KSHV.

Main Methods:

  • Treatment of PEL cells with AZD2461 and UCN-01.
  • Analysis of DNA damage response pathways, cell proliferation, and viral replication.
  • Assessment of p53/p21, c-Myc, RAD51, and KSHV lytic cycle activation.

Main Results:

  • The combination therapy reduced PEL cell proliferation and altered DNA damage response.
  • AZD2461/UCN-01 activated p53/p21, downregulated c-Myc, and reduced RAD51 expression.
  • The treatment induced KSHV lytic cycle activation, which was counteracted by p21 inhibition.

Conclusions:

  • The combination of AZD2461 and UCN-01 demonstrates therapeutic potential against PEL by impairing DNA repair and cell proliferation.
  • Targeting p21 offers a dual benefit by reducing viral replication and enhancing anti-cancer effects.
  • This strategy highlights the potential of DNA damage induction and repair inhibition for treating aggressive lymphomas.
Keywords:
AZD2461DDRKSHVPELRAD51UCN-01c-Mycp53

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