HIV‐1 integrase inhibitor raltegravir promotes DNA damage‐induced apoptosis in multiple myeloma

Abstract

Raltegravir, the first integrase inhibitor approved for the treatment of HIV infection, has been implicated as a promising potential in cancer treatment. Therefore, the present study aimed to investigate the repurposing of raltegravir as an anticancer agent and its mechanism of action in multiple myeloma (MM). Human MM cell lines (RPMI‐8226, NCI H929, and U266) and normal peripheral blood mononuclear cells (PBMCs) were cultured with different concentrations of raltegravir for 48 and 72 h. Cell viability and apoptosis were then measured by MTT and Annexin V/PI assays, respectively. Protein levels of cleaved PARP, Bcl‐2, Beclin‐1, and phosphorylation of histone H2AX were detected by Western blotting. In addition, the mRNA levels of V(D)J recombination and DNA repair genes were analyzed using qPCR. Raltegravir treatment for 72 h significantly decreased cell viability, increased apoptosis, and DNA damage in MM cells while having minimum toxicity on cell viability of normal PBMCs approximately from 200 nM (0.2 μM; p < .01 for U66 and p < .0001 for NCI H929 and RPMI 8226 cells). Furthermore, raltegravir treatment altered the mRNA levels of V(D)J recombination and DNA repair genes. We report for the first time that treatment with raltegravir is associated with decreased cell viability, apoptosis induction, DNA damage accumulation, and alteration of mRNA expression of genes involved in V(D)J recombination and DNA repair in MM cell lines, all of which show its potential for anti‐myeloma effects. Hence, raltegravir may significantly impact the treatment of MM, and further studies are required to confirm its efficacy and mechanism of action in more detail in patient‐derived myeloma cells and in‐vivo models.

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines

“…The induction of ferroptosis has been suggested to arise from either DNA damage or the release of reactive oxygen species [3,71]. As previously reported [72], raltegravir, an integrase inhibitor, was able to induce regulated cell death in multiple myeloma by damaging DNA. Consequently, cabotegravir induce apoptosis and/or ferroptosis in melanoma cell lines, causing DNA damage.…”

Identification of co-expressed central genes and transcription factors in acute myocardial infarction and diabetic nephropathy

“…As the first integrase inhibitor approved for the treatment of HIV infection, Raltegravir is gradually being discovered to have effects other than anti-HIV. Studies have shown that Raltegravir may be effective in treating multiple myeloma by promoting DNA damage-induced apoptosis [ 49 ]. Another study showed that Raltegravir was effective in treating human T-cell lymphoblastic virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraplegia (HAM/TSP).…”