Potential New Therapies "ROS-Based" in CLL: An Innovative Paradigm in the Induction of Tumor Cell Apoptosis

Abstract

Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm.

Keywords: apoptosis; chronic lymphocytic leukemia; lymphoproliferative diseases; oxidative stress; reactive oxygen species.

Figure 1

Summary of target therapies in CLL: The primary pathogenic pathways of CLL and the medicines that target BTK, PI3K, and Bcl-2. BCR signaling is triggered by self-binding or antigen recognition; Lyn encourages spleen tyrosine kinase (Syk) activation. After that, Syk initiates the assembly of a multi-component “signalosome” that consists of Btk (inhibited by ibrutinib, acalabrutinib), PI3K (inhibited by idelalisib), and PLCγ2. Anti-apoptotic molecules such as Bcl-2 (inhibited by venetoclax), Bcl-XL, and Mcl-1 are upregulated in CLL, whereas pro-apoptotic molecules Bax and Bak are sequestered, and the intrinsic apoptosis pathway is inhibited [37]. “Created with BioRender.com”.

Figure 2

Elevated levels of ROS and tumor cells apoptosis: ROS disrupt the membrane of the mitochondria and activate the mitochondrial electron transport chain (ETC), leading to the release of cytochrome c and the opening of the permeability transition pore (PTP). Cytochrome-c, together with Apaf-1 and pro-caspase-9, produces “apoptosomes” in the cytosol. These apoptosomes trigger caspase-9, which then initiates executioner caspases like caspase-3 or 7. This ultimately leads to the breakdown of proteins and the occurrence of apoptotic cellular death. “Created with BioRender.com”.

Figure 3

CLL and microenvironment: BMSCs and NLC, present in lymph nodes, emit potent chemotactic signals that facilitate the attraction and retention of circulating CLL cells inside the tissues. Stromal cells release chemokines such CCL3 and CCL4 to recruit more CD3þ T cells and monocytes, so creating a more favorable milieu. The recruited T cells are mostly CD4þ/CD154(CD40L)þ and have a significant impact on the stimulation of CLL cells, partly through the involvement of the TNF superfamily member CD40. CD40 ligation, when combined with Tcell–derived cytokines like IL4 and IL8, increases the survival, growth, and resistance to the standard immunochemotherapy of CLL. “Created with BioRender.com”.

Figure 4

Overview of factors modulating oxidative stress and apoptosis in CLL cells: (a) ATM may be able to manage oxidative stress by exerting an influence on NRF2. Moreover, cells lacking ATM in CLL exhibited decreased antioxidant levels and increased mitochondrial ROS. (b) S70pBcl2 reduces the binding of Bcl-2 to the mitochondrial complex-IV subunit-5A, leading to an impact on the function of mitochondrial complex-IV, respiration, and the production of ROS. (c) In the De Rosa et al. investigation, the lymphocytes of 30 consecutive patients with CLL exhibited elevated levels of TSPO expression, decreased levels of TBARS, NO, which are two indicators of oxidative stress and caspase-3 activity. After six months of therapy, the ratio of TSPO to mitochondria in 24 out of 30 patients with CLL approximated that of healthy individuals. Significantly, the six patients who exhibited resistance to therapy also demonstrated elevated TSPO levels, reduced caspase 3 activity, and decreased TBARS levels. (d) The level of p66Shc expression was observed to have an inverse correlation with chemokine receptor expression and the degree of organ infiltration. “Created with BioRender”.