mitoxantrone

P1, N=20, Suspended, University of Washington | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

The combination of mitoxantrone (MTX) and curcumin (Cur) optimized ICD properties in TC-1 tumor cells, as evidenced by increased release of "find me" signals, such as HMGB1 and ATP, and enhanced exposure of the "eat me" signal, CALR, compared to either MTX or Cur alone...Furthermore, the ICD cells in combination with E7-HBcAg VLPs or E7-Q11 nanofibers induced more intense effector cell responses to the antigen included in the nanovaccines, as well as a broad spectrum of antigens provided by tumor cells, and significantly suppressed the growth of established tumors compared with either ICD cells, VLPs, or nanofibers alone. In conclusion, the combination of ICD cells and nanosized antigens produced synergistic antitumor effects and elicited robust and comprehensive antitumor immunity, presenting an attractive strategy for developing personalized tumor vaccines.

In this chapter, we provide straightforward methodologies to isolate DCs from murine bone marrow (bone marrow-derived DCs, BMDCs), induce immunogenic apoptosis in murine MCA205 fibrosarcoma cells using ICD inducer mitoxantrone (MTX), co-cultivate BMDCs with the MTX-treated cancer cells, and to assess the activation and maturation status of BMDCs by flow cytometric-assisted quantification of co-stimulatory molecules (MHC II, CD86, CD80) expressed on the plasma membrane of BMDCs. With minor adjustments, the same protocol can be implemented to other cancer cell lines or to analyze the phenotypic status of non-professional APCs.

Loading the hydrogel with mitoxantrone (MTX) and metformin (MET) further enhances the therapeutic effect by combining chemotherapy with PD-L1 downregulation. Mechanistically, KFM promotes PD-L1 degradation via a ubiquitin-dependent pathway. This "carrier-free" delivery system expands the role of supramolecular hydrogels beyond passive carriers to active immunotherapeutic agents, offering a promising new strategy for cancer therapy.

Additionally, 0.005% Tween 20 effectively reversed resistance to paclitaxel, vincristine, doxorubicin, and mitoxantrone in various cancer MDR cell lines. In the in vivo depression-like behavior model, 0.01% Tween 20 markedly enhanced the antidepressant and anxiolytic effects of fluoxetine. Given its strong inhibitory effects on P-gp, MRP1, and BCRP, along with its capacity to reverse drug resistance both in vitro and in vivo, Tween 20 is a compelling candidate for tackling transporter-mediated drug resistance.

P=N/A, N=114, Recruiting, Army Medical Center of PLA; Army Medical Center of PLA

P3, N=158, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

Our work demonstrates for the first time that the degree of GBM differentiation influences BBB permeability. The crosstalk between GBM cells that release IL-6 and BBB cells that respond by activating STAT3, controls the expression of ABC transporters and TJ proteins on BBB. These results may pave the way for novel therapeutic tools to tune BBB permeability and improve drug delivery to GBM.

P2, N=52, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

This reprogramming was characterized by a significant increase in the density of tumor-infiltrating cytotoxic T lymphocytes(CTLs), ultimately prolonging survival. Therefore, this research proposes a promising approach to trigger immunogenic cell death collaboratively, aiming to boost the tumor CTLs infiltration for anticancer immunotherapy.

Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients.

Differences in specific cell infiltration can lead to increased sensitivity of the immune-inflamed subgroup to anti-tumor drugs. The proposed lncRNA model holds great promise to assess the immune landscapes and therapeutic reactions of TNBC patients.

P2, N=54, Completed, Gilead Sciences | Trial primary completion date: Oct 2023 --> Mar 2024

For further effectively sensitizing CRC to immunotherapy, we have engineered a pH-sensitive zeolitic imidazolate framework-8 (CS/NPs), capable of efficient cGAS-STING pathway activation and immune checkpoint blockade, by encapsulating the chemotherapeutic mitoxantrone (MTX) and immunomodulator thymus pentapeptide (TP5) and tailoring with tumor-targeting chondroitin sulfate (CS)...Moreover, the damaged double-stranded DNA during MTX treatment activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which works together with TP5 induced the proliferation and differentiation of T lymphocytes and dendritic cells to further enhance the anti-CRC immune response. Therefore, CS/NPs efficiently sensitize cells to chemotherapy and stimulate systemic antitumor immune responses both in vitro and in vivo, representing a promising strategy to increase the feasibility of CRC immunotherapy.

P3, N=371, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Aug 2024 --> Dec 2024

P2, N=70, Recruiting, St. Jude Children's Research Hospital | Trial primary completion date: Mar 2025 --> Dec 2026

Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

In this study, we report the fabrication of a zinc-phenolic nanocapsule (RMP@Cap), which is loaded with mitoxantrone (MTO) and anti-PD-L1 antibodies (aPD-L1) and coated with erythrocyte membrane, for TNBC immunotherapy...Furthermore, the incorporation of a camouflaged erythrocyte membrane coating enables nanocapsules to achieve prolonged in vivo circulation, resulting in improved tumor accumulation for effective antitumor therapy. This study demonstrates a synergistic therapeutic modality involving pyroptosis, coupled with the simultaneous activation and cyclic amplification of the STING pathway in immunotherapy.

P1, N=0, Withdrawn, Medical College of Wisconsin | N=36 --> 0 | Initiation date: May 2024 --> Aug 2024 | Not yet recruiting --> Withdrawn

Recent research has particularly been focused on traditional anthracycline chemo drugs, such as doxorubicin and mitoxantrone. Additionally, MPLA helps T cell priming by activating antigen-presenting cells. This intricate interplay culminates in a synergistic effect, ultimately resulting in an augmented and potentiated anticancer chemo-immunotherapeutic liposomal treatment.

Non-toxic concentrations of RN486 remarkably increased the sensitivity of ABCG2-overexpressing cancer cells to conventional anticancer drugs mitoxantrone and topotecan. Our studies propose that RN486 can antagonize ABCG2-mediated MDR in cancer cells via down-regulating the expression level of ABCG2 protein, reducing ATPase activity of ABCG2 transporter, and inhibiting the transporting function. RN486 could be potentially used in conjunction with chemotherapy to alleviate MDR mediated by ABCG2 in cancer.

As far as we know, this was the first study made in old mice with a clinically relevant dose of MTX, evaluating its long-term cardiac effects. Even two months after MTX exposure, changes in metabolic fingerprint occurred, highlighting enduring cardiac effects that may require clinical vigilance.

Flow analysis of the tumor microenvironment and draining lymph nodes reveals an increased proportion of matured dendritic cells and activation of T cells. In summary, the research provided a reference and alternative approach to induce cancer pyroptosis for clinical antitumor therapy based on engineered cellular nanovesicles and chemotherapy.

P1, N=30, Recruiting, University of Colorado, Denver | Not yet recruiting --> Recruiting

P3, N=280, Active, not recruiting, Children's Oncology Group | Trial completion date: Jun 2024 --> Jul 2025

In this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells...Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1. These data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis.

P1, N=130, Completed, Amgen | Active, not recruiting --> Completed

P2, N=42, Not yet recruiting, Fudan University

During HSCT, haematopoietic cells are exposed to a complex mix of cytokines, so to determine if IL-6 was integral in a chemotherapy-induced bystander effect, we attempted to inhibit IL-6 from HS-5 cells using resatorvid or siRNA, treated with chlorambucil or mitoxantrone, and then co-cultured with bystander TK6 cells. Our data suggests that exposure to high IL-6 (in the absence of inflammatory cells) has potential to induce genetic damage and may contribute to de novo tumorigenesis post-CS. We suggest that for individuals with a pro-inflammatory profile, anti-IL-6 therapy may be an appropriate intervention to prevent complications post-CS.

P2, N=240, Not yet recruiting, Guangdong Provincial People's Hospital

In this study, we find that dorsomorphin (also known as compound C or BML-275) potently inhibits the transporter activity of ABCG2, thereby preserving the chemotherapeutic agents mitoxantrone and doxorubicin to antagonize MDR in ABCG2-overexpressing colorectal cancer cells. Additionally, dorsomorphin does not alter ABCG2 protein expression. The results of molecular docking studies show that dorsomorphin is bound stably to the ABCG2-binding pocket, suggesting that dorsomorphin is a potent ABCG2 inhibitor that attenuates ABCG2-mediated MDR in colorectal cancer.

P1, N=26, Completed, Medical College of Wisconsin | Active, not recruiting --> Completed | Trial completion date: Oct 2024 --> May 2024

The activation of p53-dependent apoptosis pathways was vividly expressed, evidenced by the upregulation of Bax and increased pattern of Caspase-3 cleavage. This effect was pronounced upon transfection and induction with DPP IR Mtx @Lipo NPs, particularly in comparison to non-transfected malignant breast cancer 4T1 cells.

P1, N=48, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P1, N=30, Not yet recruiting, University of Colorado, Denver

On the other hand, for ABCC1, the majority of key mutations were present in the inactive nucleotide-binding domain, followed by the drug transport channel and membrane-facing regions, highlighting the importance of the inactive nucleotide-binding domain in facilitating indirect drug efflux in ABCC1. The identified key mutations in endometrial cancer and mapped common mutations present across different types of cancers in ABCB1, ABCC1, and ABCG2 will facilitate the design and discovery of inhibitors targeting unexplored structural regions of these transporters and re-engineering of these transporters to tackle chemoresistance.

P1, N=49, Completed, Wake Forest University Health Sciences | Phase classification: P2 --> P1

These results indicate that melatonin negatively modulates the cell survival of spheres derived from CF41.Mg cells, in a way that is independent of its MT1 receptor. These effects did not counteract the resistance to doxorubicin and mitoxantrone, even though the hormone negatively regulates the gene expression of MDR1 and ABCG2.

P2, N=41, Completed, Massachusetts General Hospital | Active, not recruiting --> Completed

Moreover, marein can significantly sensitize the ABCG2-expressing tumor cells to chemotherapeutic drugs such as topotecan, mitoxantrone, and Olaparib. This study reveals a novel role and mechanism of marein in modulating drug resistance, and may have important implications in treatment of cancers that are resistant to chemotherapeutic drugs that belong to the substrates of ABCG2 transporters.

P2, N=16, Active, not recruiting, Robert Redner, MD | Completed --> Active, not recruiting | Trial completion date: Feb 2023 --> Dec 2028