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      LTe2 induces cell apoptosis in multiple myeloma by suppressing AKT phosphorylation at Thr308 and Ser473

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          Abstract

          Multiple myeloma (MM) is a highly heterogeneous hematological malignancy originating from B lymphocytes, with a high recurrence rate primarily due to drug resistance. 2-((1H-indol-3-yl)methyl)-3-((3-((1H-indol-3-yl)methyl)-1H-indol-2-yl)methyl)-1H-indole (LTe2), a tetrameric indole oligomer, possesses a wide range of anticancer activities through various mechanisms. Here, we aim to explore the anti-tumor efficiency and potential downstream targets of LTe2 in MM. Its bioactivity was assessed by employing MTT assays, flow cytometry, and the 5TMM3VT mouse model. Additionally, transcriptomic RNA-seq analysis and molecular dynamics (MD) experiments were conducted to elucidate the mechanism underlying LTe2 induced MM cell apoptosis. The results demonstrated that LTe2 significantly inhibited MM cell proliferation both in vitro and in vivo, and revealed that LTe2 exerts its effect by inhibiting the phosphorylation of AKT at the Thr308 and Ser473 sites. In summary, our findings highlight the potential of LTe2 as a novel candidate drug for MM treatment and provided a solid foundation for future clinical trials involving LTe2.

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          Most cited references40

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          Cancer statistics, 2022

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.
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            The Hallmarks of Cancer

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              Multiple myeloma

              Multiple myeloma is a malignancy of terminally differentiated plasma cells, and patients typically present with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine. The diagnosis of multiple myeloma is made when clear end-organ damage attributable to the plasma cell proliferative disorder or when findings that suggest a high likelihood of their development are present. Distinguishing symptomatic multiple myeloma that requires treatment from the precursor stages of monoclonal gammopathy of undetermined significance and smouldering multiple myeloma is important, as observation is the standard for those conditions. Much progress has been made over the past decade in the understanding of disease biology and individualized treatment approaches. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have joined the traditional armamentarium (corticosteroids, alkylating agents and anthracyclines) and, along with high-dose therapy and autologous haemopoietic stem cell transplantation, have led to deeper and durable clinical responses. Indeed, an increasing proportion of patients are achieving lasting remissions, raising the possibility of cure for this disease. Success will probably depend on using combinations of effective agents and treating patients in the early stages of disease, such as patients with smouldering multiple myeloma.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2393950Role: Role: Role: Role:
                Role: Role: Role:
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                URI : https://loop.frontiersin.org/people/690494Role: Role: Role: Role: Role:
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                14 September 2023
                2023
                : 13
                : 1269670
                Affiliations
                [1] 1 Nanjing Hospital of Chinese Medicine and School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine , Nanjing, China
                [2] 2 State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine , Nanjing, China
                [3] 3 Department of Gynecology, Jiangsu Province Hospital Affiliated Hospital of Nanjing Unviersity of Chinese Medicina , Nanjing, China
                Author notes

                Edited by: Yun Dai, First Affiliated Hospital of Jilin University, China

                Reviewed by: Fumou Sun, University of Arkansas for Medical Sciences, United States; Jin Zhu, Nanjing Medical University, China

                *Correspondence: Ye Yang, yangye876@ 123456sina.com ; Liping Lin, lplin@ 123456njucm.edu.cn ; Qin Zhang, 2200732@ 123456sina.com

                †These authors have contributed equally to this work

                Article
                10.3389/fonc.2023.1269670
                10539572
                37781194
                0775a81f-ac26-4a75-862e-37078e14df67
                Copyright © 2023 Zhang, Qian, Jiang, Yang, Zhou, Zhang, Lin and Yang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 July 2023
                : 30 August 2023
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 40, Pages: 11, Words: 3725
                Funding
                This work was supported by National Natural Science Foundation of China (82073721).
                Categories
                Oncology
                Original Research
                Custom metadata
                Cancer Molecular Targets and Therapeutics

                Oncology & Radiotherapy
                multiple myeloma,indole oligomer,lte2,akt,phosphorylation,apoptosis
                Oncology & Radiotherapy
                multiple myeloma, indole oligomer, lte2, akt, phosphorylation, apoptosis

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