Evaluating the Effectiveness of the Tumor-Initiating Stem Cells Eradication Strategy on the Example of Human Glioblastoma Cell Line U87

Долгова, Е. В.; Potter, Ekaterina A.; Proskurina, Anastasia S.; Николин, В. П.; Попова, Н. А.; Romanenko, Margarita V.; Netyosov, S. V.; Taranov, Oleg S.; Efremov, Yaroslav R.; Zavyalov, L. E.; Ostanin, А. А.; Черных, Е. Р.; Bogachev, Sergey S.

doi:10.37469/0507-3758-2019-65-6-904-919

Cited by 3 publications

(8 citation statements)

References 41 publications

(53 reference statements)

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“…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).…”

Section: Cmld Cp-based Chemotherapymentioning

confidence: 99%

“…At the core of Karanahan technology and CMLD CP-based chemotherapy is the use of DNAmix and CP. Their combination is rationally motivated and has been shown to be effective in “incurable” cancers, such as Krebs-2, U-87 xenografts, and B cell lymphomas in mice ( 6 , 8 , 78 , 80 , 81 ).…”

Section: Dnamix and Cp Treatments Are Core Elements Of The Karanahan Technology And Cmld Cp-based Chemotherapymentioning

confidence: 99%

“…Only cancer cells comprising a TAMRA+ population of TISCs are capable of stable engraftment in mice. Cancer cells that are TISC-depleted (cell sorting or selective TISC killing by CP and DNAmix) fail to engraft in syngeneic or immunodeficient mice ( 7 , 78 ). Notably, there is no contribution of the host immunity, as cytostatic drug treatment occurs ex vivo (another cross-linking cytostatic drug, MMC) prior to engraftment.…”

Section: Dnamix and Cp Treatments Are Core Elements Of The Karanahan Technology And Cmld Cp-based Chemotherapymentioning

confidence: 99%

“…In our study, complete elimination of Krebs-2 tumors in mice could only be achieved via CP/DNAmix-based targeting of TISCs. This approach was also effective in a xenogeneic setting, with human U-87 glioblastoma cells being used as a model ( 7 , 78 ). Our studies have firmly established that single or metronomic injections of CP and DNAmix are inefficient in treating such animals.…”

Section: Dnamix and Cp Treatments Are Core Elements Of The Karanahan Technology And Cmld Cp-based Chemotherapymentioning

confidence: 99%

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

Proskurina¹,

Ruzanova²,

Останин³

et al. 2021

Transl Cancer Res TCR

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Objective We describe experimental and theoretical premises of a powerful cancer therapy based on the combination of three approaches. These include (I) in situ vaccination (intratumoral injections of CpG oligonucleotides and anti-OX40 antibody); (II) chronometric or metronomic low-dose cyclophosphamide (CMLD CP)-based chemotherapy; (III) cancer stem cell-eradicating therapy referred to as Karanahan (from the Sanskrit kāraṇa [“source”] + han [“to kill”]). Background In murine models, the first two approaches are particularly potent in targeting immunogenic tumors for destruction. In situ vaccination activates a fully fledged anticancer immune response via an intricate network of ligand–receptor–cytokine interactions. CMLD CP-based chemotherapy primarily targets the suppressive tumor microenvironment and activates tumor-infiltrating effectors. In contrast, Karanahan technology, being aimed at replicative machinery of tumor cells (both stem-like and committed), does not depend on tumor immunogenicity. With this technology, mice engrafted with ascites and/or solid tumors can be successfully cured. There is a significant degree of mechanistic and therapeutic overlap between these three approaches. For instance, the similarities shared between in situ vaccination and Karanahan technology include the therapeutic procedure, the cell target [antigen-presenting cells (APC) and dendritic cells (DC)], and the use of DNA-based preparations (CpG and DNAmix). Features shared between CMLD CP-based chemotherapy and Karanahan technology are the timing and the dose of the cytostatic drug administration, which lead to tumor regression. Methods The following keywords were used to search PubMed for the latest research reporting successful eradication of transplantable cancers in animal models that relied on approaches distinct from those used in the Karanahan technology: eradication of malignancy, cure cancer, complete tumor regression, permanently eradicating advanced mouse tumor, metronomic chemotherapy, in situ vaccination, immunotherapy, and others. Conclusion We hypothesize, therefore, that very potent anticancer activity can be achieved once these three therapeutic modalities are combined into a single approach. This multimodal approach is theoretically curative for any type of cancer that depends on the presence of tumor-inducing cancer stem cells, provided that the active therapeutic components are efficiently delivered into the tumor and the specific biological features of a given patient’s tumor are properly addressed. We expect this multimodal approach to be primarily applicable to late-stage or terminal cancer patients who have...

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Section: Cmld Cp-based Chemotherapymentioning

confidence: 99%

Section: Dnamix and Cp Treatments Are Core Elements Of The Karanahan Technology And Cmld Cp-based Chemotherapymentioning

confidence: 99%

Section: Dnamix and Cp Treatments Are Core Elements Of The Karanahan Technology And Cmld Cp-based Chemotherapymentioning

confidence: 99%

Section: Dnamix and Cp Treatments Are Core Elements Of The Karanahan Technology And Cmld Cp-based Chemotherapymentioning

confidence: 99%

See 2 more Smart Citations

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

Proskurina¹,

Ruzanova²,

Останин³

et al. 2021

Transl Cancer Res TCR

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show abstract

“…In summary, it can be concluded that low/medium-dose intermittent metronomic CP chemotherapy, which relies on both the timing of repairing CP-induced DNA ICLs and that of TISCs synchronization (a variant of Karanahan , but without the use of DNA-mix), has 3 special features to mention. Triple consecutive exposures to CP results in (1) large-scale apoptosis of the bulk of tumor cells independently on tumor type and origin 55 , 56 ; (2) synchronization of tumor cells (including TISCs) and their accumulation in G2/М with following transition into G1, which is observed as shifts in cell cycle peaks 57 (on the day when TISCs synchronously exit the cell cycle arrest, the terminal exposure to CP, leading to either complete or significant eradication of TISCs, 58 , 59 is administered); and (3) depletion of immunosuppressive regulatory T cells, repolarization of myeloid-derived suppressor cells to tumor reactive one and consequent activation of effector lymphocytes. 53 , 54 …”

Section: Introductionmentioning

confidence: 99%

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

Proskurina

Kupina

Efremov

et al. 2022

Breast Cancer�(Auckl)

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Introduction: Karanahan, a cancer treatment technology aimed at eradicating tumor-initiating stem cells, has already proven effective in 7 tumor models. Karanahan comprises the following procedures: (1) collecting surgical specimens, (2) determining the duration of the DNA repair process in tumor cells exposed to a cross-linking cytostatic agent, and (3) determining the time point, when cells, including tumor-initiating stem cells, are synchronized in the certain phase of the cell cycle after triple exposure to the cytostatic, becoming vulnerable for the terminal treatment, which is supposed to completely eliminate the rest of survived tumor-initiating stem cells. Determining these basic tumor properties allows to design the schedule for the administration of a cross-linking cytostatic and a complex composite DNA preparation. Being conducted in accordance with the schedule designed, Karanahan results in the large-scale apoptosis of tumor cells with elimination of tumor-initiating stem cells. Methods: Breast tumor specimens were obtained from patients, and basic tumor properties essential for conducting Karanahan therapy were determined. Results: We report the first use of Karanahan in patients diagnosed with breast cancer. Technical details of handling surgical specimens for determining the essential Karanahan parameters (tumor volume, cell number, cell proliferation status, etc) have been worked out. The terminally ill patient, who was undergoing palliative treatment and whose tumor specimen matched the required criteria, received a complete course of Karanahan. Conclusions: The results of the treatment conducted indicate that Karanahan technology has a therapeutic potency and can be used as a breast cancer treatment option.

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Chronometric Administration of Cyclophosphamide and a Double-Stranded DNA-Mix at Interstrand Crosslinks Repair Timing, Called “Karanahan” Therapy, Is Highly Efficient in a Weakly Immunogenic Lewis Carcinoma Model

Ruzanova

Proskurina

Efremov

et al. 2022

Pathol. Oncol. Res.

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Background and Aims: A new technology based on the chronometric administration of cyclophosphamide and complex composite double-stranded DNA-based compound, which is scheduled in strict dependence on interstrand crosslinks repair timing, and named “Karanahan”, has been developed. Being applied, this technology results in the eradication of tumor-initiating stem cells and full-scale apoptosis of committed tumor cells. In the present study, the efficacy of this novel approach has been estimated in the model of Lewis carcinoma.Methods: To determine the basic indicative parameters for the approach, the duration of DNA repair in tumor cells, as well as their distribution along the cell cycle, have been assessed. Injections were done into one or both tumors in femoral region of the engrafted mice in accordance with the developed regimen. Four series of experiments were carried out at different periods of time. The content of poorly differentiated CD34+/TAMRA+ cells in the bone marrow and peripheral blood has been determined. Immunostaining followed by the flow cytometry was used to analyze the subpopulations of immune cells.Results: The high antitumor efficacy of the new technology against the developed experimental Lewis carcinoma was shown. It was found that the therapy efficacy depended on the number of tumor growth sites, seasonal and annual peculiarities. In some experiments, a long-term remission has been reached in 70% of animals with a single tumor and in 60% with two tumors. In mice with two developed grafts, mobilization capabilities of both poorly differentiated hematopoietic cells of the host and tumor stem-like cells decrease significantly. Being applied, this new technology was shown to activate a specific immune response. There is an increase in the number of NK cell populations in the blood, tumor, and spleen, killer T cells and T helper cells in the tumor and spleen, CD11b+Ly-6C+ and CD11b+Ly-6G+ cells in the tumor. A population of mature dendritic cells is found in the tumor.Conclusion: The performed experiments indicate the efficacy of the Karanahan approach against incurable Lewis carcinoma. Thus, the discussed therapy is a new approach for treating experimental neoplasms, which has a potential as a personalized anti-tumor therapeutic approach in humans.

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Evaluating the Effectiveness of the Tumor-Initiating Stem Cells Eradication Strategy on the Example of Human Glioblastoma Cell Line U87

Cited by 3 publications

References 41 publications

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

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

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

Chronometric Administration of Cyclophosphamide and a Double-Stranded DNA-Mix at Interstrand Crosslinks Repair Timing, Called “Karanahan” Therapy, Is Highly Efficient in a Weakly Immunogenic Lewis Carcinoma Model

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