Approbation of the Cancer Treatment Approach Based on the Eradication of TAMRA+ Cancer Stem Cells in a Model of Murine Cyclophosphamide Resistant Lymphosarcoma

Abstract

Background/Aim: We previously have described the "3+1" tumors cure approach consisting of individual time schedule of cyclophosphamide and dsDNA preparation administrations. The aim of the study was to adapt the "3+1" approach based on eradication of cancer stem cells to the model of murine ascitic cyclophosphamide-resistant lymphosarcoma (RLS). Materials and Methods: Adaptation of the "3+1" approach includes the identification of the timing to disrupt the tumorigenic potential of a certain tumor. Results: The proposed therapeutic scheme allowed complete reduction of primary RLS ascites in experimental animals. However, reduction of primary ascites due to the complementary action of cyclophosphamide and dsDNA was inevitably followed by the development of a secondary one, most likely arising from a solid carcinomatous formation in the peritoneal wall. Conclusion: The "3+1" approach resulted in the elimination of cancer stem cells, and, as a consequence, in the complete reduction of RLS ascites.Malignant neoplasms rank second in the world after cardiovascular disorders in overall mortality rates. Recent studies indicate a much higher complexity of the disease than previously thought. The main characteristic of this complexity determining the unpredictable response of neoplasms to a variety of therapeutic procedures and the difficulties in their cure is the heterogeneity of malignant cells that include a subpopulation of almost "indestructible" cells, which possess an incredible survival and proliferative potency, and is designated as tumor-initiating stem cells or cancer stem cells (CSCs) (1, 2).The main hallmarks of cancer stem cells are their capabilities of (1) self-renewal in through unlimited replicative cycles, (2) producing a progeny of committed cells with high proliferative activity, but incapable of inducing a new tumor, and (3) retaining a potency to induce new tumors with similar histological properties in a series of transplantations (3). CSCs possess a number of features allowing their dominance in co-existence with organism: self-sufficiency in proliferative stimuli (4), reduced sensitivity to anti-proliferative ones (5), immortalization (6, 7), dedifferentiation (8), genomic instability (9), increased efflux and metabolism of xenobiotics (10, 11), reversed "Warburg effect" (12, 13), suppression of pro-apoptotic signals ( 14), as well as stimulation of pathways causing apoptosis evasion (15). Another essential for disease development property of CSCs is their migratory capacity, allowing exit into the bloodstream, and formation of new growth foci in distant organs (16)(17)(18)(19)(20). Thus, the aforementioned properties of CSCs are such that they create 795

Efficacy of the new therapeutic approach in curing malignant neoplasms on the model of human glioblastoma

“…The first three exposures result in the large-scale caspase-activated DNase-dependent apoptosis of committed and partially stem-like tumor cells, as we have demonstrated in Krebs-2 and some other experimental tumors. The fourth terminal exposure is supposed to completely eliminate the remaining tumor cells, including the TAMRA+ CSCs, observed in the Krebs-2 model 28 , 31 , 33 .…”

“…Based on these findings, we have developed the approach allowing the synchronization and accumulation of CSCs in the certain cell cycle phase when they are very sensitive to treatment. Further, this approach, termed “Karanahan” or “3 + 1”, has been converted into the full-scale universal CSCs eradication technology 27 – 31 .…”

Theoretical premises of a “three in one” therapeutic approach to treat immunogenic and nonimmunogenic cancers: a narrative review

“…In parallel, addition of the DNAmix leads to a massive lysis of committed cancer cells. This technology has been successfully tested on several experimental mouse and human cancers and in 3 pilot clinical cases (6,8,(76)(77)(78)(79).…”

“…This technology has been successfully tested on several experimental mouse and human cancers and in 3 pilot clinical cases ( 6 , 8 , 76 - 79 ).…”

Karanahan: A Potential New Treatment Option for Human Breast Cancer and Its Validation in a Clinical Setting

“… 45 Because CP targets and destroys mainly the bulk of committed tumor cells, the tumor-protecting properties of the tumor-associated stroma, which both suppresses the immune cells activity and enhances the immunologic resistance of the tumor, facilitate the survival and proliferation of chemoresistant clones originating from TISCs, which intrinsically are almost completely resistant to CP. 28 , 40 , 41 , 43 - 50 At the same time, low/medium-dose metronomic administration of CP as a monodrug exerts a stimulating effect on immune cells, especially tumor-infiltrating ones such as natural killer cells, dendritic cells, natural killer T cells, CD4+, CD8+, and B cells. It is also typical of this therapeutic approach that it deprives CD25+/FOXP3+ regulatory T cells from the tumor node and switches tumor-associated macrophage polarization from М2 to М1.…”