bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–11–21
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities.
  2. A novel CD123-targeted therapeutic peptide loaded by micellar delivery system combats refractory acute myeloid leukemia.
  3. Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival.
  4. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.
  5. Synergistic effect of chidamide and venetoclax on apoptosis in acute myeloid leukemia cells and its mechanism.
  6. Engineering T cell memory for antitumor immunity.
  7. Review of cancer cell resistance mechanisms to apoptosis and actual targeted therapies.
  8. Keeping up with venetoclax for leukemic malignancies: key findings, optimal regimens and clinical considerations.
  9. Targeting Phosphatases and Kinases: How to Checkmate Cancer.
  10. Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
  1. Chemotherapy. 2021 Nov 12. 1-13
    The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities.
    Noorhan Ghanem, Chirine El-Baba, Khaled Araji, Riyad El-Khoury, Julnar Usta, Nadine Darwiche.
       BACKGROUND: Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect.
    SUMMARY: The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. Key Message: Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients' response to cancer therapy.
    Keywords:  Cancer; Metabolism; Pentose phosphate pathway
    DOI:  https://doi.org/10.1159/000519784
  2. J Hematol Oncol. 2021 Nov 13. 14(1): 193
    A novel CD123-targeted therapeutic peptide loaded by micellar delivery system combats refractory acute myeloid leukemia.
    Shilin Xu, Meichen Zhang, Xiaocui Fang, Jie Meng, Haiyan Xing, Doudou Yan, Jian Liu, Yanlian Yang, Tao Wen, Weiqi Zhang, Jianxiang Wang, Chen Wang, Haiyan Xu.
      Acute myeloid leukemia (AML) is a common malignant heterogeneous hematopoietic disease with very low average 5-year survival rate due to the refractory feature and high rate of relapse. CD123 is highly expressed on multiple types of AML cells, especially leukemia stem cells, and closely associated with the poor prognosis of AML. Aiming to meet the urgent demand to targeted therapeutics for the refractory AML patients, herein we synthesize a CD123 antagonistic peptide (PO-6) loaded in nanomicelles (mPO-6), and investigated its therapeutic effect and pharmacokinetics on a lab-established refractory AML mice model (AE & CKITD816V). It is shown that the PO-6 can effectively bind to the CD123+ AML cells and the micellar formulation mPO-6 increases the dissolution stability and the specific binding capacity. When injected intravenously, mPO-6 significantly prolongs the survival of the refractory AML mice by interfering CD123/IL-3 axis, evidenced by the down regulation of phosphorylation of STAT5 and PI3K/AKT and the inhibition of activated NF-κB in the nucleus, as well as by the analysis results of next generation RNA-sequencing (RNA-seq) with the bone marrow of the AML mice. The antagonistic effect leads to the significantly reduction of AML cells infiltration in the bone marrow of the AML mice. In conclusion, mPO-6 could provide a potent antagonistic therapeutic approach for targeted treatment of AML.
    Keywords:  Acute myeloid leukemia; Antagonistic peptide; CD123; Micelle; Targeting
    DOI:  https://doi.org/10.1186/s13045-021-01206-y
  3. Oxid Med Cell Longev. 2021 ;2021 1341604
    Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival.
    Brittney Joy-Anne Foo, Jie Qing Eu, Jayshree L Hirpara, Shazib Pervaiz.
      Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.
    DOI:  https://doi.org/10.1155/2021/1341604
  4. Nat Nanotechnol. 2021 Nov 18.
    Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.
    Tanmoy Saha, Chinmayee Dash, Ruparoshni Jayabalan, Sachin Khiste, Arpita Kulkarni, Kiran Kurmi, Jayanta Mondal, Pradip K Majumder, Aditya Bardia, Hae Lin Jang, Shiladitya Sengupta.
      Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.
    DOI:  https://doi.org/10.1038/s41565-021-01000-4
  5. Ann Transl Med. 2021 Oct;9(20): 1575
    Synergistic effect of chidamide and venetoclax on apoptosis in acute myeloid leukemia cells and its mechanism.
    Gangping Li, Dongbei Li, Fangfang Yuan, Cheng Cheng, Lin Chen, Xudong Wei.
       Background: Acute myeloid leukemia (AML) is a hematological malignancy with a low remission rate and high recurrence rate. Overexpression of the antiapoptotic protein Bcl-2 is associated with a lower overall survival rate in AML patients. Venetoclax (ABT199) is a selective inhibitor of Bcl-2 that has a significant effect in AML, but single-drug resistance often occurs due to the high expression of Mcl-1 protein. Studies have confirmed that chidamide can downregulate the expression levels of Bcl-2 and Mcl-1 and induce apoptosis.
    Methods: This study aimed to use AML cell lines and primary cells to study the effects of venetoclax and chidamide combination therapy on AML cell apoptosis, the cell cycle, and changes in related signaling pathways in vitro; establish an AML mouse model to observe the efficacy and survival time of combination therapy in vivo; and analyze the drug effects with multi-omics sequencing technology. The changes in gene and protein expression before and after treatment were examined to clarify the molecular mechanism driving the synergistic effect of the two drugs.
    Results: (I) Both venetoclax and chidamide promoted apoptosis in AML cell lines and primary cells in a time- and concentration-dependent manner. The effect was further enhanced when the two drugs were combined, and a synergistic effect was observed (combination index <1). (II) At both the mRNA and protein levels, the expression of Mcl-1 was upregulated by venetoclax and downregulated by chidamide, and the expression of Mcl-1 decreased further after combination treatment. (III) Transcriptome sequencing showed that differentially expressed genes in the combination group compared with the venetoclax monotherapy group were mainly enriched in the PI3K-AKT pathway and JAK2/STAT3 pathway. Moreover, qRT-PCR and Western blot confirmed these results. (IV) The combination therapy group exhibited significantly inhibited disease progression and a prolonged survival time among AML mice.
    Conclusions: Chidamide combined with venetoclax synergistically promoted apoptosis in AML cell lines and primary cells by inhibiting activation of the PI3K/AKT pathway and JAK2/STAT3 pathway.
    Keywords:  Chidamide; acute myeloid leukemia (AML); apoptosis; mechanism; venetoclax
    DOI:  https://doi.org/10.21037/atm-21-5066
  6. Trends Pharmacol Sci. 2021 Nov 13. pii: S0165-6147(21)00218-2. [Epub ahead of print]
    Engineering T cell memory for antitumor immunity.
    Aladdin M Bhuiyan, Michael Dougan.
      Cancer therapy with the T cell growth factor interleukin (IL)-2 is limited by low response rates and toxicity. Multiple protein engineering strategies have attempted to improve IL-2 therapy, typically through enhanced IL-2 receptor (IL-2R) binding. Intriguingly, Mo et al. show that an IL-2R partial agonist may dramatically improve IL-2 responses by altering T cell differentiation.
    Keywords:  CAR T cell; IL-2 mimetic; IL-2 receptor; T cell exhaustion
    DOI:  https://doi.org/10.1016/j.tips.2021.11.003
  7. J Cell Biochem. 2021 Nov 17.
    Review of cancer cell resistance mechanisms to apoptosis and actual targeted therapies.
    Merve Kulbay, Adeline Paimboeuf, Derman Ozdemir, Jacques Bernier.
      The apoptosis pathway is a programmed cell death mechanism that is crucial for cellular and tissue homeostasis and organ development. There are three major caspase-dependent pathways of apoptosis that ultimately lead to DNA fragmentation. Cancerous cells are known to highly regulate the apoptotic pathway and its role in cancer hallmark acquisition has been discussed over the past decades. Numerous mutations in cancer cell types have been reported to be implicated in chemoresistance and treatment outcome. In this review, we summarize the mutations of the caspase-dependant apoptotic pathways that are the source of cancer development and the targeted therapies currently available or in trial.
    Keywords:  apoptosis; cell mutations; resistance; targeted therapy
    DOI:  https://doi.org/10.1002/jcb.30173
  8. Expert Rev Clin Pharmacol. 2021 Nov 18.
    Keeping up with venetoclax for leukemic malignancies: key findings, optimal regimens and clinical considerations.
    Maria Siddiqui, Marina Konopleva.
       INTRODUCTION: Venetoclax has transformed the treatment landscape in hematologic malignancies, especially in elderly population. With high rates of remission, deep and durable responses, and safe toxicity profile, venetoclax in combination therapy has been extremely effective, garnering accelerated approval and becoming standard of care in lymphoid and myeloid malignancies.
    AREAS COVERED: The role of venetoclax in the intrinsic apoptotic pathway is covered. This includes preclinical and clinical experience of venetoclax monotherapy and combination therapy in relapsed/refractory and frontline CLL, AML, ALL and high-risk MDS, with an emphasis on key clinical trials and efficacy of combination regimens in distinct mutational landscapes. Strategies to mitigate myelosuppression, manage dose adjustments and infectious complications are addressed.
    EXPERT OPINION: Targeting BCL-2 offers a safe and highly effective adjunct to available therapies in hematologic malignancies. Despite success and frequent utilization of venetoclax, several resistance mechanisms have been elucidated, prompting development of novel combinatorial strategies. Further, on-target myelosuppression of venetoclax is a key obstacle in clinical practice, requiring diligent monitoring and practice-based knowledge of dose modifications. Despite these limitations, venetoclax has gained tremendous popularity in hematologic-oncology, becoming an integral component of numerous combination regimes, with ongoing plethora of clinical trials encompassing standard chemotherapy, targeted agents and immune-based approaches.
    Keywords:  acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; myelodysplastic syndrome; venetoclax
    DOI:  https://doi.org/10.1080/17512433.2021.2008239
  9. Front Cell Dev Biol. 2021 ;9 690306
    Targeting Phosphatases and Kinases: How to Checkmate Cancer.
    Alice Turdo, Caterina D'Accardo, Antonino Glaviano, Gaetana Porcelli, Cristina Colarossi, Lorenzo Colarossi, Marzia Mare, Naida Faldetta, Chiara Modica, Giuseppe Pistone, Maria Rita Bongiorno, Matilde Todaro, Giorgio Stassi.
      Metastatic disease represents the major cause of death in oncologic patients worldwide. Accumulating evidence have highlighted the relevance of a small population of cancer cells, named cancer stem cells (CSCs), in the resistance to therapies, as well as cancer recurrence and metastasis. Standard anti-cancer treatments are not always conclusively curative, posing an urgent need to discover new targets for an effective therapy. Kinases and phosphatases are implicated in many cellular processes, such as proliferation, differentiation and oncogenic transformation. These proteins are crucial regulators of intracellular signaling pathways mediating multiple cellular activities. Therefore, alterations in kinases and phosphatases functionality is a hallmark of cancer. Notwithstanding the role of kinases and phosphatases in cancer has been widely investigated, their aberrant activation in the compartment of CSCs is nowadays being explored as new potential Achille's heel to strike. Here, we provide a comprehensive overview of the major protein kinases and phosphatases pathways by which CSCs can evade normal physiological constraints on survival, growth, and invasion. Moreover, we discuss the potential of inhibitors of these proteins in counteracting CSCs expansion during cancer development and progression.
    Keywords:  cancer stem cell; kinase; phosphatase; phosphatase and kinase inhibitors; targeted therapies
    DOI:  https://doi.org/10.3389/fcell.2021.690306
  10. Autophagy. 2021 Nov 15. 1-3
    Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
    Payel Mondal, Christina Towers.
      Mitochondria are critical organelles that maintain cellular metabolism and overall function. The catabolic pathway of autophagy plays a central role in recycling damaged mitochondria. Although the autophagy pathway is indispensable for some cancer cell survival, our latest study shows that rare autophagy-dependent cancer cells can adapt to loss of this core pathway. In the process, the autophagy-deficient cells acquire unique dependencies on alternate forms of mitochondrial homeostasis. These rare autophagy-deficient clones circumvent the lack of canonical autophagy by increasing mitochondrial dynamics and by recycling damaged mitochondria via mitochondrial-derived vesicles (MDVs). These studies are the first to implicate MDVs in cancer cell metabolism although many unanswered questions remain about this non-canonical pathway.
    Keywords:  Cancer; mitochondrial fusion; mitochondrial-derived vesicles; mitophagy; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1999562
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