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Chemical Biology & Drug Design Aug 2023Raltegravir, the first integrase inhibitor approved for the treatment of HIV infection, has been implicated as a promising potential in cancer treatment. Therefore, the...
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.
Topics: Humans; Multiple Myeloma; Raltegravir Potassium; HIV-1; Cell Line, Tumor; HIV Infections; Leukocytes, Mononuclear; Apoptosis; RNA, Messenger; Integrase Inhibitors; DNA Damage; Cell Proliferation
PubMed: 37094820
DOI: 10.1111/cbdd.14237 -
AIDS (London, England) Oct 2023We sought to compare virologic outcomes on antiretroviral therapy (ART) between people with HIV (PWH) also treated for tuberculosis in the different countries who... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We sought to compare virologic outcomes on antiretroviral therapy (ART) between people with HIV (PWH) also treated for tuberculosis in the different countries who participated to two randomized trials.
DESIGN
Pooled analysis of two randomized clinical trials.
METHODS
In the phase II Reflate TB and phase III Reflate TB2 trials conducted in Brazil, Côte d'Ivoire, Mozambique and Vietnam, ART-naïve PWH treated for tuberculosis were randomized to receive raltegravir or efavirenz. We assessed country differences in baseline characteristic using Wilcoxon tests and chi-square, or Fisher's exact test. We used logistic regression to analyze determinants of virologic success, defined as week-48 plasma HIV-1 RNA <50 copies/ml.
RESULTS
Of 550 participants (140 from Brazil, 170 from Côte d'Ivoire, 129 from Mozambique and 111 from Vietnam) with median baseline HIV-1 RNA of 5.4 log 10 copies/ml, 362 (65.8%) achieved virologic success at week 48. Virologic success rates were: 105/140 (75.0%) in Brazil, 99/170 (58.2%) in Côte d'Ivoire, 84/129 (65.1%) in Mozambique and 74/111 (66.7%) in Vietnam ( P = 0.0233). Baseline HIV-1 RNA, but not the country, was independently associated with virologic success: baseline HIV-1 RNA ≥500 000 copies/ml (reference), HIV RNA <100 000 copies/ml odds ratio 3.12 [95% confidence interval (CI) 1.94; 5.01] and HIV-1 RNA 100 000-499 999 copies/ml odds ratio: 1.80 (95% CI 1.19; 2.73). Overall, 177/277 (63.9%) patients treated with raltegravir and 185/273 (67.9%) patients treated with efavirenz had a plasma HIV-1 RNA <50 copies/ml at week 48.
CONCLUSIONS
Virologic response to antiretroviral therapy in PWH with TB varied across countries but was mainly driven by levels of pretreatment HIV-1 RNA.
Topics: Humans; HIV Infections; Raltegravir Potassium; Tuberculosis; RNA, Viral; Viral Load; Anti-HIV Agents
PubMed: 36928120
DOI: 10.1097/QAD.0000000000003521 -
Critical Reviews in Analytical Chemistry 2024The advent of HIV-Integrase inhibitors (IN) has marked a significant impact on the lives of HIV patients. Since the launch of the first anti retro-viral drug... (Review)
Review
The advent of HIV-Integrase inhibitors (IN) has marked a significant impact on the lives of HIV patients. Since the launch of the first anti retro-viral drug "Azidothymidine" to the recent advances of IN inhibitors, about 27.4 million people benefit by antiretroviral therapy (ART). The path had been challenging due to many crossroads, leading to the discovery of newer targets. One such recent ART target is Integrase. Use of Integrase inhibitors has surpassed the usage of all other ART owing to a strong barrier to resistance and have been reported to be the first-line therapy. Raltegravir, Elvitegravir, Dolutegravir and Bictegravir are US FDA approved IN inhibitors. The high usage of ART created an opportunity to study various analytical techniques for IN inhibitors. Hitherto, no review encompassing all IN inhibitors is presented. Herein, this review describes the analytical techniques employed for IN inhibitors estimation and quantification reported in the literature and official compendia. Literature suggests that most studies focus on LC-MS/MS and HPLC methods for drug estimation, and few reports suggest spectrophotometric, spectrofluorimetric and electrochemical methods. Furthermore, the review presents the techniques that describe the quantification of integrase drugs in various matrices. Although, antiretroviral drugs are extensively used but data suggests that limited studies have been conducted for determination of impurity profile and stability. This therefore, presents a scope to detect and validate impurities in order to meet ICH guidelines for their limits and further to improve the quality and safety of antiretroviral drugs.
Topics: Humans; Raltegravir Potassium; HIV Integrase Inhibitors; HIV Infections; HIV-1; Chromatography, Liquid; Tandem Mass Spectrometry; Integrases; Pyridones; Oxazines; Amides; Piperazines; Quinolones; Heterocyclic Compounds, 3-Ring
PubMed: 35617468
DOI: 10.1080/10408347.2022.2080493