ArticlePublisher preview availableLiterature Review

Membrane Lipid Replacement for reconstituting mitochondrial function and moderating cancer-related fatigue, pain and other symptoms while counteracting the adverse effects of cancer cytotoxic therapy

Authors:
Garth Nicolson at The Institute for Molecular Medicine
Garth Nicolson
  • The Institute for Molecular Medicine
Gonzalo Ferreira at Universidad de la República de Uruguay
Gonzalo Ferreira
Read publisher preview
Download citation
To read the full-text of this research, you can request a copy directly from the authors.

Abstract and Figures

Cancer-related fatigue, pain, gastrointestinal and other symptoms are among the most familiar complaints in practically every type and stage of cancer, especially metastatic cancers. Such symptoms are also related to cancer oxidative stress and the damage instigated by cancer cytotoxic therapies to cellular membranes, especially mitochondrial membranes. Cancer cytotoxic therapies (chemotherapy and radiotherapy) often cause adverse symptoms and induce patients to terminate their anti-neoplastic regimens. Cancer-related fatigue, pain and other symptoms and the adverse effects of cancer cytotoxic therapies can be safely moderated with oral Membrane Lipid Replacement (MLR) glycerolphospholipids and mitochondrial cofactors, such as coenzyme Q10. MLR provides essential membrane lipids and precursors to maintain mitochondrial and other cellular membrane functions and reduces fatigue, pain, gastrointestinal, inflammation and other symptoms. In addition, patients with a variety of chronic symptoms benefit from MLR supplements, and MLR also has the ability to enhance the bioavailability of nutrients and slowly remove toxic, hydrophobic molecules from cells and tissues.
Figures - available from: Clinical & Experimental Metastasis
This content is subject to copyright. Terms and conditions apply.
A preview of this full-text is provided by Springer Nature.
Learn more
Content available from Clinical & Experimental Metastasis
This content is subject to copyright. Terms and conditions apply.
Vol.:(0123456789)
Clinical & Experimental Metastasis
https://doi.org/10.1007/s10585-024-10290-6
REVIEW
Membrane Lipid Replacement forreconstituting mitochondrial
function andmoderating cancer‑related fatigue, pain andother
symptoms whilecounteracting theadverse effects ofcancer cytotoxic
therapy
GarthL.Nicolson1,2 · GonzaloFerreiradeMattos3
Received: 7 October 2023 / Accepted: 25 April 2024
© The Author(s), under exclusive licence to Springer Nature B.V. 2024
Abstract
Cancer-related fatigue, pain, gastrointestinal and other symptoms are among the most familiar complaints in practically
every type and stage of cancer, especially metastatic cancers. Such symptoms are also related to cancer oxidative stress and
the damage instigated by cancer cytotoxic therapies to cellular membranes, especially mitochondrial membranes. Cancer
cytotoxic therapies (chemotherapy and radiotherapy) often cause adverse symptoms and induce patients to terminate their
anti-neoplastic regimens. Cancer-related fatigue, pain and other symptoms and the adverse effects of cancer cytotoxic
therapies can be safely moderated with oral Membrane Lipid Replacement (MLR) glycerolphospholipids and mitochondrial
cofactors, such as coenzyme Q10. MLR provides essential membrane lipids and precursors to maintain mitochondrial and
other cellular membrane functions and reduces fatigue, pain, gastrointestinal, inflammation and other symptoms. In addition,
patients with a variety of chronic symptoms benefit from MLR supplements, and MLR also has the ability to enhance the
bioavailability of nutrients and slowly remove toxic, hydrophobic molecules from cells and tissues.
Keywords Cancer cytotoxic therapy· Oxidative stress· Mitochondria· Membrane phospholipids · Cancer treatment side
effects
Abbreviations
CRF Cancer-related fatigue
CoQ10 Coenzyme Q10
∆p Proton electrical/chemical gradient
∆Ψm Mitochondrial inner membrane electrical/
chemical gradient
ETC Electron transport chain
GI Gastrointestinal
GRAS Generally regarded as safe
lysoPC Lysophosphatidylcholine
MIM Mitochondrial inner membrane
MLR Membrane lipid replacement
NSAIDs Non-steroidal, anti-inflammatory drugs
PC Phosphatidylcholine
PI(4,5)P2 Phosphatidylinositol 4,5 bisphosphate
RNS Reactive nitrogen species
PS Phosphatidylserine
ROS Reactive oxygen species
TRP Transient receptor potential ion channel
UPC Uncoupling proteins
Introduction
Cancer‑related fatigue (CRF)
Cancer-related fatigue (CRF), pain, nausea, gastrointes-
tinal and other symptoms are often pervasive in cancer
* Garth L. Nicolson
gnicolson@immed.org
Gonzalo Ferreira de Mattos
ferreira@fmed.edu.uy
https://www.immed.org/
1 Department ofMolecular Pathology, The Institute
forMolecular Medicine, HuntingtonBeach, CA92647, USA
2 Department ofMolecular Pathology, The Institute
forMolecular Medicine, P.O. Box9355, S.LagunaBeach,
CA92652, USA
3 Laboratory ofIon Channels, Biological Membranes andCell
Signaling, Department ofBiophysics, Facultad de Medicina,
Universidad de La República, Montevideo, Uruguay
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
ResearchGate has not been able to resolve any citations for this publication.
Cardiotoxic effects of chemotherapeutic agents with special emphasis on cisplatin
Article
Full-text available
  • Dec 2023
Cisplatin (CPT) is a long-standing widely used chemotherapeutic alkylating agent. Its main mechanism of action is by damaging the DNA, causing strand breaks which inhibit cell proliferation. In addition, they also alter ion channel function, intracellular calcium, and free radical production. Although these additional mechanisms of action may contribute to their chemotherapeutic action, they frequently cause adverse reactions, and originate mechanisms of drug resistance. In this review, we focus on the properties of the adverse effects of CPT on the heart. In isolated hearts a biphasic effect of CPT on inotropism can be described, which is positive at concentrations below 5 μM and negative at higher concentrations. These effects could be explained by the ability of CPT to promote changes in Cav1.2 channels and intracellular Ca2+ in isolated cardiomyocytes. The biphasic inotropic behavior of the heart to CPT has good correlation with its actions on Cav1.2 currents and intracellular Ca2+.These findings suggest that CPT has several sites of impact on the heart, and that Cav1.2 channels and intracellular Ca2+ dysfunction are key players in the heart’s adverse reactions to CPT.
View
Nanomedicine in cancer therapy
Article
Full-text available
  • Aug 2023
Cancer remains a highly lethal disease in the world. Currently, either conventional cancer therapies or modern immunotherapies are non-tumor-targeted therapeutic approaches that cannot accurately distinguish malignant cells from healthy ones, giving rise to multiple undesired side effects. Recent advances in nanotechnology, accompanied by our growing understanding of cancer biology and nano-bio interactions, have led to the development of a series of nanocarriers, which aim to improve the therapeutic efficacy while reducing off-target toxicity of the encapsulated anticancer agents through tumor tissue-, cell-, or organelle-specific targeting. However, the vast majority of nanocarriers do not possess hierarchical targeting capability, and their therapeutic indices are often compromised by either poor tumor accumulation, inefficient cellular internalization, or inaccurate subcellular localization. This Review outlines current and prospective strategies in the design of tumor tissue-, cell-, and organelle-targeted cancer nanomedicines, and highlights the latest progress in hierarchical targeting technologies that can dynamically integrate these three different stages of static tumor targeting to maximize therapeutic outcomes. Finally, we briefly discuss the current challenges and future opportunities for the clinical translation of cancer nanomedicines.
View
Drug-induced oxidative stress in cancer treatments: Angel or devil?
Article
Full-text available
  • May 2023
Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells generally represent a higher oxidant level, which suggests a dual therapeutic strategy by regulating redox status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, pro-oxidant therapy exhibits a great anti-cancer capability, attributing to a higher oxidant accumulation within cancer cells, whereas antioxidant therapy to restore redox homeostasis has been claimed to fail in several clinical practices. Targeting the redox vulnerability of cancer cells by pro-oxidants capable of generating excessive reactive oxygen species (ROS) has surfaced as an important anti-cancer strategy. However, multiple adverse effects caused by the indiscriminate attacks of uncontrolled drug-induced OS on normal tissues and the drug-tolerant capacity of some certain cancer cells greatly limit their further applications. Herein, we review several representative oxidative anti-cancer drugs and summarize their side effects on normal tissues and organs, emphasizing that seeking a balance between pro-oxidant therapy and oxidative damage is of great value in exploiting next-generation OS-based anti-cancer chemotherapeutics.
View
Microbial Translocation Disorders: Assigning an Etiology to Idiopathic Illnesses
Article
Full-text available
  • Jan 2023
  • Appl Microbiol
Gut microbes are immunologically tolerated in the gastrointestinal tract but trigger aggressive immune responses upon translocation across the gut barrier. Although oral tolerance, a physiological process that dampens immune responses to food proteins and commensal microbiota, remains poorly defined, significant progress was made during and after the Human Immunodefi-ciency Virus epidemic in the 1980s and the discovery of regulatory T cells in 1995. Additional insight was gained after the discoveries of innate lymphoid cells in 2008 and the functional elucidation of mucosal mast cells. Prior to the historical discovery of human pathogens, the etiologies of most human diseases were considered unknown. The same was true about many genetic disorders prior to the Human Genome Project. Here, we hypothesize that many of the remaining idiopathic conditions , including autoimmune, fibroproliferative, and neuropsychiatric diseases as well as some cancers , can be considered microbial translocation disorders triggered by the host immune responses to extraintestinal gut microbes and/or their constituent parts. In addition to microbial translocation, we also discuss potential interventions for intestinal barrier rehabilitation, including antibodies against tumor necrosis factor-like ligand 1A and membrane lipid replacement supplements.
View
A Comprehensive Overview of the Complex Role of Oxidative Stress in Aging, The Contributing Environmental Stressors and Emerging Antioxidant Therapeutic Interventions
Article
Full-text available
  • Jun 2022
Introduction Aging is a normal, inevitable, irreversible, and progressive process which is driven by internal and external factors. Oxidative stress, that is the imbalance between prooxidant and antioxidant molecules favoring the first, plays a key role in the pathophysiology of aging and comprises one of the molecular mechanisms underlying age-related diseases. However, the oxidative stress theory of aging has not been successfully proven in all animal models studying lifespan, meaning that altering oxidative stress/antioxidant defense systems did not always lead to a prolonged lifespan, as expected. On the other hand, animal models of age-related pathological phenotypes showed a well-correlated relationship with the levels of prooxidant molecules. Therefore, it seems that oxidative stress plays a more complicated role than the one once believed and this role might be affected by the environment of each organism. Environmental factors such as UV radiation, air pollution, and an unbalanced diet, have also been implicated in the pathophysiology of aging and seem to initiate this process more rapidly and even at younger ages. Aim The purpose of this review is to elucidate the role of oxidative stress in the physiology of aging and the effect of certain environmental factors in initiating and sustaining this process. Understanding the pathophysiology of aging will contribute to the development of strategies to postpone this phenomenon. In addition, recent studies investigating ways to alter the antioxidant defense mechanisms in order to prevent aging will be presented. Conclusions Careful exposure to harmful environmental factors and the use of antioxidant supplements could potentially affect the biological processes driving aging and slow down the development of age-related diseases. Maybe a prolonged lifespan could not be achieved by this strategy alone, but a longer healthspan could also be a favorable target.
View
The effects of Membrane Lipid Replacement with NTFactor® Lipids on increasing the bioavailability of three test nutrients
Article
Full-text available
  • May 2022
Introduction: Previous studies indicated that lipids and nanostructured materials may improve the uptake of nutrients with moderate bioabsorption properties. Objectives: This study evaluated the effects of Membrane Lipid Replacement with NTFactor® Lipids (NTFL) on bioabsorption of three poorly to moderately absorbed nutrients (quercetin, curcumin and coenzyme Q10) utilizing the Caco-2 epithelial cell permeability model. Methods: Transfer across a Caco-2 epithelial cell layer has become a reference standard in the pharmaceutical and nutraceutical industries for in vitro prediction of in vivo human intestinal absorption and bioavailability of orally administered substances. The degree of bioabsorption of the test materials was assessed by monitoring the concentrations of the test materials on each side of the Caco-2 monolayers by liquid chromatography and mass spectroscopy (LCMS/MS analysis).Results: When NTFL was added to each of the three test nutrients, there was increased absorption and transfer across a Caco-2 cell layer in a dose-dependent manner for the three nutrients. When compared individually, CoQ10 with NTFL showed the most significant increase in absorption (2.01-times more compared to controls without NTFL, p=0.0011) at a concentration of NTFL of 10 mg/mL. NTFL also increased absorption and transfer across a Caco-2 cell layer of the other test nutrients, but these results did not achieve the same level of significance. Discussion: A variety of Oral membrane lipid replacement supplements with NTFL, such as various vitamins, minerals and nutrients, have been designed to reduce fatigue, improve health conditions, and protect cellular and especially mitochondrial membranes from damage. Here we used NTFL to demonstrate improvements in absorption and bioavailability of three nutrients. Conclusion: Using the Caco-2 bioabsorption and bioavailability in vitro model we found that NTFL could enhance absorption, bioavailability and uptake of nutrients while providing its own clinically demonstrated health benefits. Keywords: Phospholipids, Membrane Lipid Replacement, CoQ10, curcumin, quercetin, bioavailability, absorption, permeability, Caco2, bio-uptake, bioabsorption, glycerolphospholipids, intestinal absorption
View
Membrane Lipid Replacement with Glycerolphospholipids Slowly Reduces Self-Reported Symptom Severities in Chemically Exposed Gulf War Veterans
Article
Full-text available
  • Apr 2022
Background: Chemically exposed veterans of the 1991 Gulf War have few options for treatment of conditions and symptoms related to their chemical exposures. Membrane Lipid Replacement (MLR) with oral membrane glycerolphospholipids is a safe and effective method for slowly removing hydrophobic organic molecules from tissues, while enhancing mitochondrial function and decreasing the severity of certain signs and symptoms associated with multi-symptom illnesses. Methods: A preliminary open-label study utilizing 20 male veterans who were deployed to combat areas, exposed to environmental toxic chemicals and subsequently diagnosed with Gulf War Illnesses (GWI) were utilized. These subjects took 6 g per day oral glycerolphospholipids for 6 months, and the severities of over 100 signs and symptoms were self-reported at various times using illness survey forms. Results: In the sixteen patients that fully complied and completed the study, there were gradual and significant reductions of symptom severities in categories related to fatigue, pain, musculoskeletal, nasopharyngeal, breathing, vision, sleep, balance, and urinary, gastrointestinal and chemical sensitivities. There were no adverse incidents during the study, and the all-natural oral study supplement was extremely well tolerated. Conclusions: MLR with oral glycerolphospholipids appears to be a simple, safe and potentially effective method of slowly reducing the severities of multiple symptoms in chemically exposed veterans.
View
Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity
Article
Full-text available
  • Jan 2022
Significance Radiotherapy is one of the most common forms of cancer treatment used today. Its impact in directly killing cancer cells, and on antitumour immunity, is well recognized, but its effect on immune cell–cancer cell interactions is not fully understood. Here, we show that irradiation of cancer cells surprisingly leads to resistance against immune cell cytotoxicity. This was mediated by a reduced susceptibility to the pore-forming protein perforin. Resistance manifested as a reduction in both necrotic death following osmotic lysis and apoptotic death following granzyme B uptake. Overall, these data establish a form of treatment-induced resistance to lymphocyte cytotoxicity. These findings have significant implications for the optimal design of radiotherapy–immunotherapy protocols.
View
Non-pharmacologic interventions for improving cancer-related fatigue (CRF): A systematic review of systematic reviews and pooled meta-analysis
Article
  • Mar 2023
  • SEMIN ONCOL
Introduction: Literature encloses numerous systematic reviews (SRs) on nonpharmacologic interventions for improving cancer-related fatigue (CRF). The effect of these interventions remains controversial, and the available SRs have not been synthesized yet. We conducted a systematic synthesis of SRs and meta-analysis to determine the effect of nonpharmacologic interventions on CRF in adults. Material and methods: We systematically searched 4 databases. The effect sizes (standard mean difference) were quantitatively pooled using a random-effects model. Chi-squared (Q) and I-square statistics (I²) tested the heterogeneity. Results: We selected 28 SRs, including 35 eligible meta-analyses. The pooled effect size (standard mean difference, 95% CI) was -0.67 (-1.16, -0.18). The subgroup analysis by types of interventions showed a significant effect in all the investigated approaches (complementary integrative medicine, physical exercise, self-management/e-health interventions). Conclusions: There is evidence that nonpharmacologic interventions are associated with CRF reduction. Future research should focus on testing these interventions on specific population clusters and trajectories. Prospero registration: CRD42020194258.
View
Chemotherapy induced oxidative stress in the ovary: drug-dependent mechanisms and potential interventions
Article
  • Dec 2022
Cancer incidence and relative survival are expected to increase over the next few decades. With the majority of patients receiving combinatorial chemotherapy, an increasing proportion of patients experience long-term side effects from treatment— including reproductive disorders and infertility. A limited number of studies have examined mechanisms of single-agent chemotherapy-induced gonadotoxicity, with chemotherapy-induced oxidative stress being implicated in the loss of reproductive functions. Current methods of female fertility preservation are costly, invasive, only moderately successful, and seldom presented to cancer patients. The potential of antioxidants to alleviate chemotherapy has been overlooked at a time when it is becoming increasingly important to develop strategies to protect reproductive functions during chemotherapy. This review will summarize the importance of reactive oxygen species homeostasis in reproduction, chemotherapy-induced mitochondrial dysfunction in oocytes, chemotherapy-induced oxidative stress, and several promising natural adjuvants.
View