-
Journal For Immunotherapy of Cancer Aug 2023Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade....
BACKGROUND
Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade. However, this effect is still clinically rare and improvements are highly desirable. We investigated whether triple combination with a low dose of clinically approved liposomal doxorubicin (Doxil) could augment abscopal responses compared with RT/αPD-1 and Doxil/αPD-1. We also investigated whether the enhanced abscopal responses depended on the mitochondrial DNA (mtDNA)/cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)/IFN-I pathway.
MATERIALS/METHODS
We used Doxil in combination with RT and αPD-1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated. Mechanistic studies on the role of the mtDNA/cGAS/STING/IFN-I axis were performed using inhibitors and knockout cells in vitro as well as in mice.
RESULTS
Addition of a single low dose of Doxil to RT and αPD-1 strongly enhanced the RT/αPD-1-induced abscopal effect in both models. Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and more tumor-specific CD8 T cells than RT/αPD-1 and Doxil/αPD-1, particularly in non-irradiated tumors. Coincubation of Doxil-treated and/or RT-treated tumor cells with DCs enhanced DC antigen cross-presentation which is crucial for inducing CD8 T cells. CD8 T cell depletion or implantation of cGAS-deficient or STING-deficient tumor cells abolished the abscopal effect. Doxorubicin-induced/Doxil-induced IFNβ1 markedly depended on the cGAS/STING pathway. Doxorubicin-treated/Doxil-treated tumor cells depleted of mtDNA secreted less IFNβ1, of the related T cell-recruiting chemokine CXCL10, and ATP; coincubation with mtDNA-depleted tumor cells strongly reduced IFNβ1 secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated/abscopal site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8 T cells.
CONCLUSIONS
These data show that single low-dose Doxil can substantially enhance the RT/αPD-1-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8 tumor-specific T cells particularly in abscopal tumors compared with RT/αPD-1 and Doxil/αPD-1. Moreover, they indicate that the mtDNA/cGAS/STING/IFN-I axis is important for the immunogenic/immunomodulatory doxorubicin effects. Our findings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients.
Topics: Animals; Mice; DNA, Mitochondrial; CD8-Positive T-Lymphocytes; Mitochondria; Doxorubicin
PubMed: 37640480
DOI: 10.1136/jitc-2022-006235 -
Nature Communications Mar 2024Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC...
Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.
Topics: Humans; Myeloid-Derived Suppressor Cells; Glutamine; Hematologic Neoplasms; Adenosine Triphosphate; Doxorubicin; Succinates
PubMed: 38555305
DOI: 10.1038/s41467-024-47096-9 -
Leukemia Apr 2024Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly...
Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.
Topics: Humans; Induction Chemotherapy; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Neoplasms, Second Primary; Retrospective Studies; Sulfonamides
PubMed: 38378841
DOI: 10.1038/s41375-024-02175-0 -
Advanced Science (Weinheim,... Apr 2022Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new...
Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new avenues to overcome the related problems by improving drug selectivity. It is recently shown that sonomechanical bond scission enables the remote-controlled drug release from their inactive parent macromolecules using ultrasound (US). To further expand the scope of the US-controlled drug activation strategy, herein a mechano-responsive nanoswitch for the selective activation of doxorubicin (DOX) to inhibit cancer cell proliferation is constructed. As a proof-of-concept, the synthesis, characterization, and US-responsive drug activation evaluation of the mechano-nanoswitch, which provides a blueprint for tailoring nanosystems for force-induced pharmacotherapy is presented.
Topics: Activation, Metabolic; Doxorubicin; Drug Liberation; Humans; Macromolecular Substances; Neoplasms
PubMed: 35195372
DOI: 10.1002/advs.202104696 -
Acta Oncologica (Stockholm, Sweden) Sep 2022Treatment of acute promyelocytic leukaemia has emerged as a major success in hemato-oncology. While literature from the developed world boasts of outstanding outcomes,...
BACKGROUND
Treatment of acute promyelocytic leukaemia has emerged as a major success in hemato-oncology. While literature from the developed world boasts of outstanding outcomes, there is a paucity of data from the developing world. This study aimed to assess complications and outcomes of acute promyelocytic leukaemia in a resource-constrained setting.
METHODS
We retrospectively collected data from patients diagnosed with APL from January 2016 to December 2020.
RESULTS
Sixty-four patients were treated-32 in both the Sanz high and low-risk groups. In the Sanz low-risk group, 12.5% of patients received ATRA with daunorubicin and 81.25% received ATRA with ATO. In the Sanz high-risk group, 18.8% of patients received ATRA with daunorubicin, 34.3% received ATRA with daunorubicin and ATO while 40.6% received ATRA with ATO. 56.25% of patients developed differentiation syndrome. The incidence was higher in Sanz high-risk group as compared to Sanz low-risk group. 57.4% of patients had an infection at the time of presentation. 62.5% of patients developed neutropenic fever during treatment. 17.2% of patients developed pseudotumor cerebri. The 4-year EFS and OS were 71.25 and 73.13%, respectively. Sanz low-risk group had a better 4-year EFS and OS as compared to the Sanz high-risk group. Haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes with a hazard ratio of 0.8 and 3.1, respectively. Outcomes in high-risk patients were better with the use of ATRA + ATO + daunorubicin.
CONCLUSION
In the Indian population, APL patients have a high incidence of differentiation syndrome, pseudotumor cerebri, and infections during induction. CR, EFS, and OS compared to the developed world can be achieved with optimal therapy. Low haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes. ATRA, ATO, and daunorubicin combination is the preferred protocol for treating high-risk patients.
Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin; Cohort Studies; Retrospective Studies; Pseudotumor Cerebri; Antineoplastic Agents; Daunorubicin; Syndrome; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 35950607
DOI: 10.1080/0284186X.2022.2109424 -
Journal of Medicinal Chemistry Nov 2021The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported,...
The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 μM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Coordination Complexes; Daunorubicin; Drug Resistance, Neoplasm; Drug Synergism; Gold; Humans; Triazoles
PubMed: 34670090
DOI: 10.1021/acs.jmedchem.1c01021 -
European Journal of Medicinal Chemistry Jan 2021Despite the encouraging clinical progress of chemotherapeutic agents in cancer treatment, innovation and development of new effective anticancer candidates still... (Review)
Review
Despite the encouraging clinical progress of chemotherapeutic agents in cancer treatment, innovation and development of new effective anticancer candidates still represents a challenging endeavor. With 15 million death every year in 2030 according to the estimates, cancer has increased rising of an alarm as a real crisis for public health and health systems worldwide. Therefore, scientist began to introduce innovative solutions to control the cancer global health problem. One of the promising strategies in this issue is the multitarget or smart hybrids having two or more pharmacophores targeting cancer. These rationalized hybrid molecules have gained great interests in cancer treatment as they are capable to simultaneously inhibit more than cancer pathway or target without drug-drug interactions and with less side effects. A prime important example of these hybrids, the HDAC hybrid inhibitors or referred as multitargeting HDAC inhibitors. The ability of HDAC inhibitors to synergistically improve the efficacy of other anti-cancer drugs and moreover, the ease of HDAC inhibitors cap group modification prompt many medicinal chemists to innovate and develop new generation of HDAC hybrid inhibitors. Notably, and during this short period, there are four HDAC inhibitor hybrids have entered different phases of clinical trials for treatment of different types of blood and solid tumors, namely; CUDC-101, CUDC-907, Tinostamustine, and Domatinostat. This review shed light on the most recent hybrids of HDACIs with one or more other cancer target pharmacophore. The designed multitarget hybrids include topoisomerase inhibitors, kinase inhibitors, nitric oxide releasers, antiandrogens, FLT3 and JAC-2 inhibitors, PDE5-inhibitors, NAMPT-inhibitors, Protease inhibitors, BRD4-inhibitors and other targets. This review may help researchers in development and discovery of new horizons in cancer treatment.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Benzimidazoles; Cyclic Nucleotide Phosphodiesterases, Type 5; Daunorubicin; Doxorubicin; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Molecular Targeted Therapy; Morpholines; Nicotinamide Phosphoribosyltransferase; Nitric Oxide; Pyrimidines; Quinazolines; Structure-Activity Relationship; Transcription Factors; fms-Like Tyrosine Kinase 3
PubMed: 33077264
DOI: 10.1016/j.ejmech.2020.112904 -
Journal of Chromatography. B,... Jun 2022Liposome encapsulating cytarabine (CYT) and daunorubicin (DNR) is applied for treating Acute Myeloid Leukemia (AML) patients. To evaluate and compare relationship...
Determination of free and encapsulated cytarabine and daunorubicin in rat plasma after intravenous administration of liposomal formulation using ultra-high performance liquid chromatography tandem mass spectrometry.
Liposome encapsulating cytarabine (CYT) and daunorubicin (DNR) is applied for treating Acute Myeloid Leukemia (AML) patients. To evaluate and compare relationship between the pharmacokinetics of free drug (drug which is not entrapped in liposomes) and liposome-encapsulated drug and the toxicity/efficacy, it is crucial to have trustworthy methods for separating the free and the encapsulated of the drug. In this study, methods were developed and validated to isolate and measure the free DNR/CYT (F-DNR/CYT), the encapsulated DNR/CYT (E-DNR/CYT) and the total DNR/CYT (T-DNR/CYT) in rat plasma. The methods involved solid-phase extraction (SPE) using reverse adsorbents for separating the F-DNR and E-DNR, SPE using cation exchange adsorbents for separating the E-CYT, ultrafiltration for isolating the F-CYT and protein precipitation (PPT) for releasing the T-DNR and T-CYT totally from the liposomal forms. The analytes were subsequently quantified on ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) individually with multiple reaction monitoring (MRM) mode using positive electrospray ionization (ESI). The calibration curves showed good linear relationships over the concentration range of 0.22-44 μg/mL for E-DNR and T-DNR, 2-1000 ng/mL for F-DNR, 0.5-100 μg/mL for E-CYT and T-CYT, 4-2000 ng/mL for F-CYT respectively. For all the analytes, the within-and between-run precisions were less than13.6% and the accuracies (in terms of RE%) were within -12.5%. Besides, extraction recovery, matrix effect, dilution integrity and stability were also assessed. The methods were successfully applied to investigate the pharmacokinetics in Sprague-Dawley rats following i.v. administration liposomal formulation.
Topics: Administration, Intravenous; Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Cytarabine; Daunorubicin; Humans; Liposomes; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry
PubMed: 35551041
DOI: 10.1016/j.jchromb.2022.123275 -
Nanomedicine : Nanotechnology, Biology,... Nov 2020CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute...
CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In preclinical species, this article demonstrated (1) similar release of cytarabine and daunorubicin by CPX-351 in plasma; (2) similar patterns of metabolism of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal cytarabine/daunorubicin combination; (3) prolonged tissue exposure to CPX-351; (4) dramatically different tissue distribution of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination (tissue:plasma ratios generally <1 versus >1, respectively); and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination. Together, these results provide insight into the safety profile of CPX-351, as well as mechanisms that drive the improved efficacy observed for CPX-351 versus the conventional 7 + 3 cytarabine/daunorubicin regimen in clinical studies.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Bile; Chromatography, High Pressure Liquid; Cytarabine; Daunorubicin; Dogs; Drug Combinations; Feces; Female; Half-Life; Limit of Detection; Male; Mice; Rats; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Tissue Distribution
PubMed: 32750494
DOI: 10.1016/j.nano.2020.102275 -
Journal of Biomolecular Structure &... 2022Anti-cancer daunorubicin and etoposide drugs are mostly used in chemotherapy medicine to treat a wide variety of cancers. Many of the side effects and specific delivery...
Anti-cancer daunorubicin and etoposide drugs are mostly used in chemotherapy medicine to treat a wide variety of cancers. Many of the side effects and specific delivery to a target tissue are the main challenges of using chemotherapeutic agents. To avoid serious toxic side effects and improve treatment outcomes, functionalized carbon nanotubes (f-CNTs) are considered promising nano-carriers for the delivery of chemotherapeutic drugs to cancerous cells. We examined the effects of -OH and -COO groups on CNTs surface for absorption of two anticancer drugs including daunorubicin and etoposide using molecular dynamics simulation and experimental assays. To evaluate the absorption of each drug in each CNT, the complexes of drugs/CNTs in water were simulated separately. Theoretical investigation demonstrated that CNT-OH and CNT-COO are more suitable for absorption of daunorubicin and etoposide, respectively. Experimental findings also confirmed molecular dynamics simulation results. Communicated by Ramaswamy H. Sarma.
Topics: Humans; Nanotubes, Carbon; Etoposide; Daunorubicin; Pharmaceutical Preparations; Drug Delivery Systems; Antineoplastic Agents; Neoplasms
PubMed: 34166598
DOI: 10.1080/07391102.2021.1938232