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Proteasomal adaptations to FDA-approved proteasome inhibitors: a potential mechanism for drug resistance?

With proteasome inhibitors (PIs) becoming clinically available since 2003, outcomes for patients with multiple myeloma (MM) have dramatically changed, improving quality of life and survival. Despite the impressive treatment success, however, almost all MM patients who initially respond to these PIs eventually develop resistance. Furthermore, a portion of MM patients is inherently unresponsive to the PIs. Extensive mechanistic investigations identified several non-proteasomal signaling pathways suspected to be linked to the PI resistance, for which several excellent reviews are currently availa

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… Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma. Leukemia. 2018;32:391–401. doi: 10.1038/leu.2017.212. 44. Lü S, Chen Z, Yang J, et al. …

How to Use a Prioritised Approach for Treating Hematological Disorders During the COVID-19 Pandemic in India?

The current pandemic coronavirus, SARS-CoV-2, is known to cause severe infection (COVID-19) in patients with comorbidities, particularly cancer or an immunosuppressed state. Most healthcare systems in the country are likely to be overwhelmed soon if the pandemic moves to a stage of community transmission. Currently, limited evidence is available for managing patients with hematological disorders during the COVID-19 pandemic. The current review summarises the possible challenges clinicians are likely to face, key considerations to guide decision making, and possible solutions to the anticipated

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… COVID-19 hospital as per the national policy [ 25 ] Keep low threshold for testing in immunocompromised patients Look and treat for co-infections Management according to national guidelines if tested positive [ 25 ] Monitor for drug interactions for therapies used for COVID-19 (chloroquine/remedisvir/lopinavir …

Computational proteomics to enhance personalized treatment of COVID-19 and Long COVID.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to significant global health burden, including both acute infections and persistent post-acute sequelae, also known as Long COVID (LC) in survivors. While clinical management has reduced case-fatality rates, a substantial proportion of patients develop LC, a heterogeneous syndrome with long-term symptoms. This complex continuum requires therapeutic strategies for both the acute and chronic phases. Plasma proteomics has emerged as a powerful tool in precision medicin

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… . | [ 256 ] NCT04280705 | Remdesivir | Completed (Phase 3) | [ 257 ] NCT04356937 | Tocilizumab | Completed (Phase 3) | [ 258 ] NCT04328480 | Colchicine | Completed (Phase 3) | [ 259 ] NCT04315948 | DisCoVeRy randomized controlled trial (remdesivir, lopinavir/ritonavir, interferon beta-1 A, hydroxychloroquine … The WHO Solidarity trial, which enrolled more than 11,000 patients across 30 countries, demonstrated that none of four repurposed antivirals (lopinavir, hydroxychloroquine, remdesivir, or interferon regimens) had a significant effect on outcomes in hospitalized COVID-19 patients. …

P-Glycoprotein as a Therapeutic Target in Hematological Malignancies: A Challenge to Overcome.

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review exa

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… Building upon these findings, in a study identified nelfinavir and lopinavir, HIV protease inhibitors, as effective sensitizers of highly antimitotic drug-resistant cancer cells. Notably, nelfinavir exerted its sensitizing effect through a mechanism independent of P-gp inhibition. … These findings suggest that nelfinavir and lopinavir may possess therapeutic potential as repurposed agents for overcoming drug resistance in cancer treatment [ 143 ]. …

Infectious Diseases

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The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis.

Although it has long been recognized that inflammation, a consequence of immune-driven processes, significantly impacts bone turnover, the degree of centralization of skeletal and immune functions has begun to be dissected only recently. It is now recognized that formation of osteoclasts, the bone resorbing cells of the body, is centered on the key osteoclastogenic cytokine, receptor activator of NF- κ B ligand (RANKL). Although numerous inflammatory cytokines are now recognized to promote osteoclast formation and skeletal degradation, with just a few exceptions, RANKL is now considered to be

From Lab to Clinic: Success Stories of Repurposed Drugs in Treating Major Diseases.

Drug repurposing, the process of identifying new therapeutic uses for existing drugs, has emerged as a cost-effective and time-saving alternative to traditional drug development. This strategy leverages the known pharmacological and safety profiles of approved or investigational drugs to accelerate their clinical application for other diseases. In recent years, repurposed drugs have played a crucial role in addressing treatment gaps in complex and multifactorial diseases such as cancer, neurodegenerative disorders and infectious diseases. This review highlights prominent examples where repurpo

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… Remdesivir | Antiviral | Suppressing the production of proinflammatory cytokines | [ 81 – 83 ] Cidofovir | Antiviral | Anticancer properties against ovarian and cervical cancers | [ 84 ] Oseltamivir | Antiviral | Reducing neuroinflammation severity in mice with multiple sclerosis (MS) | [ 80 , 85 ] Lopinavir … Lopinavir, an antiviral drug, was found to decrease amyloid‐beta production, a protein linked to AD [ 86 ]. …

Repurposing FDA approved drugs as possible anti-SARS-CoV-2 medications using ligand-based computational approaches: sum of ranking difference-based model selection.

The worldwide burden of coronavirus disease 2019 (COVID-19) is still unremittingly prevailing, with more than 440 million infections and over 5.9 million deaths documented so far since the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic. The non-availability of treatment further aggravates the scenario, thereby demanding the exploration of pre-existing FDA-approved drugs for their effectiveness against COVID-19. The current research aims to identify potential anti-SARS-CoV-2 drugs using a computational approach and repurpose them if possible. In the present study, we have

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… In combination, antiviral drugs such as oseltamivir, ganciclovir, lopinavir, and ritonavir have shown good efficacy under clinical trials [ 4 ]. Cytotoxic agents like etoposide and methotrexate and immunomodulators like imatinib have shown effects against COVID-19 [ 5 ]. …

Progress of immune senescence in multiple myeloma treatment resistance.

Multiple myeloma has become the second most common hematologic malignancy threatening human health with the increasing incidence in the population, and the emergence of drug resistance in its treatment has become a problem that needs to be solved urgently. Recent studies have shown that the immune system is closely related to the development of multiple myeloma, and immune senescence plays an extremely critical role in MM treatment resistance. In this paper, we review the connection between immune senescence and the development of MM and its possible role in the drug resistance of MM treatment

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… Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma. Leukemia. 2018;32(2):391–401. 10.1038/leu.2017.212. 77. Franqui-Machin R, Wendlandt EB, Janz S, Zhan F, Tricot G. …

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome.

The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specificall

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… Kaletra is a combination of Lopinavir and Ritonavir (LPV/r). This is also used as antiviral nucleotide analogs developed for the treatment of HIV/AIDS. The third option is a combination of Kaletra with Interferon. …

Liver Disease Associated with Non-Hepatitis Viruses

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… Therapy During SARS outbreaks both ribavirin and Kaletra (baby dose ritonavir/lopinavir) were tested as experimental therapy but showed limited success. …

Role of remdesivir for the treatment of COVID-19 in patients with hematologic malignancy-A narrative review and expert opinion.

BackgroundCOVID-19 remains a potentially severe condition for immunocompromised individuals, such as patients with hematologic malignancy. These patients are at increased risk of progressing to severe-critical or prolonged COVID-19. Prompt treatment with antivirals has proven effective in preventing disease progression and is recommended by current guidelines. We discuss here the position of remdesivir in the management of onco-hematologic patients infected with SARS-CoV-2 and strategies for its use.MethodsNarrative review of current evidence regarding remdesivir in the treatment of COVID-19 i

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… , open‐label, phase 3 trial that included 584 hospitalized patients with moderate COVID‐19. 33 The WHO Solidarity trial was a large, open‐label randomized study involving hospitalized patients with COVID‐19 who were assigned in equal proportions to receive one of four drugs available at that time (lopinavir …

Кардиотоксичность, вызванная множественными миэломатерапиями: механистическая конвергенция между протеиновыми ингибиторами, CAR-T и биконкретными антителами.

Сердечно-сосудистая токсичность стала важным препятствием на пути реализации полного клинического потенциала современной терапии для множественных миэломы (ММ), включая протеазонные ингибиторы (ИП), химерика антигенного рецептора Т-клеток (CAR-T) и CD3-engaging Биотипные антитела. Здесь мы обсуждаем эпидемиологию, лежащую в основе механистических путей, и новые стратегии предотвращения кардиотоксичности, вызванной терапией, в MM. На основе данных, полученных в ходе исследований по изучению мультиомики, доклинических моделей и данных наблюдений в реальном мире, мы синтезируем вклад митохондриал

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… Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (HIV)-protease inhibitors lopinavir or nelfinavir. BJU Int. 2018;121:600–9. 10.1111/bju.14083. …

Cancer, more than a "COVID-19 co-morbidity".

Patients with cancer represent a particularly vulnerable population at risk of adverse outcomes related to COVID-19. Collectively, the initial studies, including patients with and without cancer, confirmed that patients with cancer had a higher risk of complications and death related to COVID-19. Subsequent studies on patients with COVID-19 and cancer investigated patient and disease-related factors associated with COVID-19 severity and morality. Multiple interconnected factors include demographics, comorbidities, cancer-associated variables, treatment side effects, and other parameters. Howev

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… Except for remdesivir, other treatments, including hydroxychloroquine, lopinavir, ivermectin, and interferon beta-1, have not shown any effect on mortality, hospitalization, or initiation of ventilation ( 100 , 102 , 103 ). …

Advances in delivery methods of Arthrospira platensis (spirulina) for enhanced therapeutic outcomes.

Arthrospira platensis (A. platensis) aqueous extract has massive amounts of natural products that can be used as future drugs, such as C-phycocyanin, allophycocyanin, etc. This extract was chosen because of its high adaptability, which reflects its resolute genetic composition. The proactive roles of cyanobacteria, particularly in the medical field, have been discussed in this review, including the history, previous food and drug administration (FDA) reports, health benefits and the various dose-dependent therapeutic functions that A. platensis possesses, including its role in fighting against

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… In comparison to Lopinavir (−9.7 Kcal/mol) followed by Nelfinavir (−9.3 Kcal/mol), and lastly Remdesivir (−9.0 Kcal/mol). …

Repurposing drugs for highly prevalent diseases: pentoxifylline, an old drug and a new opportunity for diabetic kidney disease.

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, d

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… strategy of drug repurposing has been widely employed in recent times during the coronavirus disease 2019 (COVID-19) pandemic, witnessing the evaluation and use of several existing molecules for their therapeutic potential against coronaviruses including hydroxychloroquine, remdesivir, ivermectin, lopinavir …

The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States

Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins—whose aberrant activities govern the reprogramed state of infected-coronavirus cells—presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to establ

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… Moreover, broad availability of high-throughput screening approaches has allowed the purposing and repurposing of drugs based on their effect on virus replication( 16 – 19 ), leading to identification of several anti-coronavirus candidates, such as chloroquine, tamoxifen, dasatinib and lopinavir, among …

Revisiting potential value of antitumor drugs in the treatment of COVID-19.

Since an outbreak started in China in 2019, coronavirus disease 2019 (COVID-19) has rapidly become a worldwide epidemic with high contagiousness and caused mass mortalities of infected cases around the world. Currently, available treatments for COVID-19, including supportive care, respiratory support and antiviral therapy, have shown limited efficacy. Thus, more effective therapeutic modalities are highly warranted. Drug repurposing, as an efficient strategy to explore a potential broader scope of the application of approved drugs beyond their original indications, accelerates the process of d

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… Previous studies have confirmed that lopinavir and ritonavir are capable of inhibiting the activity of Mpro and they also show exceptional performance in clinical application [ 83 ]. Besides, more studies have been performed to screen novel inhibitors of Mpro. …

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma.

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three protea

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… Carfilzomib Resistance Due to ABCB1/MDR1 Overexpression is Overcome by Nelfinavir and Lopinavir in Multiple Myeloma . Leukemia ( 2018 ) 32 : 391 – 401 . doi: 10.1038/leu.2017.212 28676669 PMC5808083 87 Lee MJ Miller Z Park JE Bhattarai D Lee W Kim KB . …

Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, retrospective, cohort study.

BackgroundCOVID-19 has spread globally. Epidemiological susceptibility to COVID-19 has been reported in patients with cancer. We aimed to systematically characterise clinical features and determine risk factors of COVID-19 disease severity for patients with cancer and COVID-19.MethodsIn this multicentre, retrospective, cohort study, we included all adult patients (aged ≥18 years) with any type of malignant solid tumours and haematological malignancy who were admitted to nine hospitals in Wuhan, China, with laboratory-confirmed COVID-19 between Jan 13 and March 18, 2020. Enrolled patients were

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… Several clinical trials are underway to define potential roles for antiviral agents (remdesivir, lopinavir, or ritonavir) 29 and specific immunomodulators such as IL-6 receptor blockade (tocilizumab; ChiCTR2000029765) in COVID-19. …