Journal of Cancer Research
- ISSN: 2578-3726
Alexandre Tavartkiladze, Gaiane Simonia, Nana Okrostsvaridze, Pati Revazishvili, Maia Maisuradze and Givi Tavartkiladze
Cancer remains a leading cause of mortality globally, necessitating the continuous development of more effective therapeutic strategies. One of the significant challenges in cancer treatment is multidrug resistance (MDR), where cancer cells evade the cytotoxic effects of chemotherapeutic agents through mechanisms such as the overexpression of ATPbinding cassette (ABC) transporters. These transporters reduce intracellular drug concentrations, thereby diminishing the efficacy of treatments. To address this issue, AminoSineTriComplex has been formulated as an innovative natural remedy combining classical medicine and homeopathy. This complex integrates L-Sulforaphane, Sinefungin, and Fumitremorgin C, each targeting cancer cells through distinct pathways. L-Sulforaphane, a naturally occurring isothiocyanate found in cruciferous vegetables, exhibits multiple anticancer mechanisms. It inhibits histone deacetylases (HDACs), leading to the reactivation of silenced tumor suppressor genes and the downregulation of oncogenes, which disrupts cancer cell proliferation and survival. Additionally, L-Sulforaphane activates the Nrf2 pathway, increasing the expression of antioxidant proteins and reducing oxidative stress, while also suppressing the NF-κB signaling pathway to reduce inflammation. It promotes apoptosis through intrinsic and extrinsic pathways, inhibits cell cycle progression, and reduces angiogenesis by inhibiting the formation of new blood vessels necessary for tumor growth. Furthermore, L-Sulforaphane modulates host cell signaling pathways to enhance antiviral responses. Sinefungin, a nucleoside antibiotic, inhibits SAM-dependent methyltransferases, impacting the methylation of DNA, RNA, and proteins. This inhibition leads to the reactivation of tumor suppressor genes and repression of oncogenes, inducing apoptosis in cancer cells and disrupting viral replication. By altering methylation patterns, Sinefungin disrupts cellular methylation processes essential for cancer cell proliferation and survival. Fumitremorgin C, a mycotoxin, inhibits ABC transporters such as P-glycoprotein (P-gp), preventing the efflux of chemotherapeutic agents from cancer cells. This leads to increased intracellular drug concentrations, enhancing the cytotoxic effects of chemotherapeutics and promoting apoptosis. By inhibiting drug efflux pumps, Fumitremorgin C increases the susceptibility of cancer cells to chemotherapeutic agents and enhances apoptotic pathways. AminoSineTriComplex also includes essential amino acids (L-Leucine, L-Tryptophan, L-Phenylalanine, and L-Lysine) known for their pro-apoptotic and anticonvulsant properties. These amino acids stabilize neuronal membrane potential, influence neurotransmitter release, and enhance GABA receptor activity, contributing to the overall therapeutic effect. In addition, natural compounds like EGCG, Genistein, Quercetin, Apigenin, and Berberine enhance the antitumor effects by activating caspases, inducing cell cycle arrest, and modulating various signaling pathways. To evaluate the efficacy of AminoSineTriComplex, it was tested on multidrug-resistant cancer cell lines, including UFH001 (triple-negative breast cancer), CWR-R1ca (castration-recurrent prostate cancer), and HCC95 (lung squamous carcinoma). The following in vitro methods were employed to assess antitumor activity: MTT assay to measure cytotoxic effects, flow cytometry with Annexin V/PI staining to quantify apoptosis, caspase activity assays to detect activation of caspases, Western blotting for apoptotic markers, NK cell activation assays, DNA fragmentation assay (TUNEL assay), real-time PCR and RNA sequencing to analyze changes in gene expression related to apoptosis and immune activation,and immunofluorescence and confocal microscopy to visualize apoptotic markers and cell interactions. The application of AminoSineTriComplex to these cell cultures revealed significant antitumor, pro-apoptotic, and NKcell activating effects. In UFH-001 cells, a significant reduction in cell viability and induction of apoptosis was observed, along with a marked decrease in MMP expression, indicating inhibition of metastasis. CWR-R1ca cells exhibited enhanced caspase activation and increased apoptosis, along with modulation of androgen receptor splice variants, highlighting potential efficacy in castration-recurrent prostate cancer. HCC95 cells showed reduced cell proliferation and increased apoptosis, demonstrating the compound›s effectiveness in lung squamous carcinoma. The significant antitumor effects observed in these cell lines can be attributed to the multifaceted mechanisms of action of AminoSineTriComplex. The combination of L-Sulforaphane, Sinefungin, and Fumitremorgin C targets cancer cells through multiple pathways, including epigenetic modulation, inhibition of ABC transporters, and induction of apoptosis. The essential amino acids and additional natural compounds further enhance the pro-apoptotic and immune-activating effects, creating a comprehensive strategy to overcome multidrug resistance. The potential clinical applications of AminoSineTriComplex are substantial. Its ability to reduce cell viability, induce apoptosis, inhibit metastasis, and activate NK cells suggests that it can enhance the efficacy of existing chemotherapeutics and offer a novel approach to cancer treatment. By preventing the efflux of chemotherapeutic drugs from cancer cells, AminoSineTriComplex increases intracellular drug concentrations, enhancing cytotoxic effects and reducing the likelihood of cancer recurrence and metastasis. The activation of NK cells observed in co-culture experiments indicates that AminoSineTriComplex can also enhance the immune-mediated destruction of cancer cells. Further in vivo studies and clinical trials are warranted to validate these findings and explore the therapeutic potential of AminoSineTriComplex in diverse cancer types. The observed modulation of androgen receptor splice variants in CWRR1ca cells, in particular, demonstrates its potential efficacy in castration-recurrent prostate cancer, a challenging and often treatment-resistant form of cancer. Additionally, the significant decrease in MMP expression in UFH-001 and HCC95 cells suggests that AminoSineTriComplex can effectively inhibit the metastatic potential of these cancer cells. In conclusion, AminoSineTriComplex represents a promising addition to clinical and preventive medicine, offering new hope for improved cancer treatment outcomes. Its multifaceted mechanisms of action, including epigenetic modulation, inhibition of ABC transporters, and enhancement of immune responses, provide a comprehensive strategy for combating cancer›s resilience to treatment. This innovative natural remedy combining classical medicine and homeopathy has the potential to transform cancer therapy and significantly improve patient survival rates.