Summary Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor-I activation, currently under clinical trial in a variety of cancers. We have tested the combined effects of galunisertib- and interleukin-15-activated dendritic cells in an aggressive and highly metastatic murine lymphoma. Based on the tumor-draining lymph node architecture, and its histology, the combination therapy results in better prognosis, including disappearance of the disease-exacerbating regulatory T cells. Our data suggest that galunisertib significantly enhances the success of immunotherapy with IL-15-activated dendritic cells by limiting the regulatory T cells generation with consequent downregulation of regulatory T cells in the tumor-draining lymph nodes and vascularized organ like spleen. This is also associated with consistent loss p-SMAD2 and downregulation of Neuropilin-1, leading to better prognosis and positive outcome. These results connect the role of combined therapy with the consequent elimination of disease-exacerbating T regulatory cells in a metastatic murine lymphoma.

Enhanced drug localization at the tumor sites with minimal toxicity was demonstrated using dendrimer-conjugated temozolomide for treating experimental lymphoma, developed as a solid tumor. Herein, we have constructed a polyamidoamine (PAMAM) dendrimer conjugated with temozolomide to enhance the stability of the active drug metabolites, derived from the prodrug temozolomide. Our results suggest that the active drug (5-(3-methyltriazen-1-yl)­imidazole-4-carboxamide) (MTIC) (derived from temozolomide) showed stable and sustained release from the dendrimer–temozolomide conjugate, suggesting the suitability of the construct for therapy. Besides growth inhibition and direct killing, the dendrimer–temozolomide construct induced extensive apoptosis not only in parental Dalton lymphoma tumor cells but also in the doxorubicin-resistant form of the tumor cells. Dendrimer–temozolomide conjugation significantly reduced the solid tumor growth and increased the lifespan with better prognosis, including improved histopathology of the treated mice, while untreated littermates developed extensive metastasis and succumbed to death.

The 6-amino-1,3-dimethyl uracil-based azo derivative (p-carboxy phenylazouracil, L11) undergoes Cu­(II)-catalyzed cyclization to a triazole derivative, namely, 1,3-dimethyl-8-(p-carboxy phenyl) azapurine (L11P). Interestingly, the azo functionality of L11 undergoes both symmetrical and asymmetrical reductive cleavage at two different reaction conditions. The chloride salts of Mn­(II), Ni­(II), and Pd­(II) catalyze reductive cleavage of an azo moiety in an asymmetric manner, producing a new uracil hydrazine derivative (A3). On the other hand, hydrazine catalyzes symmetrical reductive cleavage of the azo moiety of L11, resulting in 5,6-diamino-1,3-dimethyl uracil (A2) along with the starting p-aminobenzoic acid (A1). Time-dependent density functional theoretical (TD-DFT) studies provide optimized geometries of L11, L11P, and A3 along with their orbital energies. The L11 and L11P bind firmly to genomic DNA of E. coli with a site size n ∼ 9 and n ∼ 8. The L11P shows anticancer activity on selected murine lymphoma cancer cell lines (DL, YAC1, and 2PK3). In addition, its antiproliferative activity is measured with several cancer cell lines and found hemocompatible toward blood cells. Corresponding molecular docking studies of L11P with caspase-3 (cysteine-aspartic proteases) unlock their mode of interaction.

Integrative medicine practices, such as Ayurveda, are popular in India and many South Asian countries, yet basic research to investigate the concepts, procedures, and medical benefits of ayurvedic products has received little attention and is not fully understood. Here, we report a functional nanodiamond-based traditional Ayurvedic herbomineral formulation, Heerak Bhasma (Ayu_ND), for the treatment of solid tumors called Dalton’s lymphoma generated in CD1 mice. Ayu_ND-mediated immunostimulation significantly reduces tumor cell proliferation and induces apoptosis aided by the active participation of dendritic cells. Immunomodulatory Ayu_ND treatment is highly immunostimulatory and drives dendritic cells to produce TNF-α. Treatment with Ayu_ND significantly reduces the tumor volume, inhibits metastasis in distant vascularized organs, and increases the life span of tumor-bearing animals compared with untreated littermates. These events were associated with elevated serum levels of the protective cytokines IFN-γ and TNF-α and downregulated the disease, exacerbating TGF-β. Ayu_ND-mediated therapeutic success was also accompanied by the depletion of regulatory T cells and enhanced vaccine-induced T-cell immunity, guided by the restoration of the memory CD8+ T-cell pool and prevention of PD-1-mediated T cell exhaustion. The results provide a basis for further evaluation of ayurvedic formulations and drug efficacy in treating cancers.

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