Assessing the Potential of MNPR-202: A Non-Cardiotoxic Anthracycline Analog in the Treatment of Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) represents the predominant aggressive lymphoma type, typically treated with a combination of rituximab and chemotherapy drugs including cyclophosphamide, doxorubicin, vincristine, and prednisone, known as R-CHOP. Despite the high response rate to this treatment, about 40% of patients experience a relapse, partly due to the intolerance of doxorubicin, particularly its cardiotoxic side effects, which are more pronounced in elderly patients. The search for anthracycline alternatives that maintain anti-cancer efficacy but reduce cardiotoxicity is therefore crucial.

Camsirubicin, a derivative of doxorubicin, has shown less cardiotoxicity in preclinical studies and clinical trials, without causing irreversible heart damage. MNPR-202, another analog of camsirubicin, has been modified to potentially overcome resistance to doxorubicin while retaining its non-cardiotoxic properties.

An in vitro study compared the effects of doxorubicin and MNPR-202 on eight DLBCL cell lines, assessing cell proliferation, apoptosis, and DNA damage. Both compounds showed similar impacts on cell growth and comparable IC50 values, but MNPR-202 was more effective at inducing apoptosis and causing DNA damage.

Further analysis of the activation of immune response pathways revealed that doxorubicin consistently induced the expression of genes related to the cGAS/STING and RIG-I pathways, whereas MNPR-202 did not.

A drug screen with nearly 200 compounds was also conducted to explore potential synergies with MNPR-202. Notably, the PLK1 inhibitor volasertib showed an antagonistic effect with doxorubicin but not as significantly with MNPR-202.

The study suggests that while doxorubicin and MNPR-202 have similar cytotoxic effects, they operate through different cellular mechanisms. MNPR-202 induces more DNA damage and apoptosis but less immune activation. The differences in drug synergies indicate that MNPR-202 could be advantageous in certain combination therapies. The results highlight the potential of MNPR-202 as a promising non-cardiotoxic anthracycline derivative for lymphoma treatment, warranting further investigation.