Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy

Kumar, Rishabh; Mishra, Anurag; Gautam, Priyanka; Feroz, Zainab; Vijayaraghavalu, Sivakumar; Likos, Eviania M.; Shukla, Girish C.; Kumar, Munish

doi:10.3390/cancers14215268

Cited by 13 publications

(7 citation statements)

References 185 publications

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“…Cellular metabolism represents a primary characteristic by orchestrating aberrant metabolic reprogramming to fulfill the increased energy requirements for sustained proliferation ( Sun et al, 2020 ). Cancer cells can evade apoptosis through aberrant metabolic regulation ( Kumar et al, 2022 ). Our findings showed that XHP induced alterations in the concentrations of multiple metabolites in PC mice, suggesting that XHP may modulate metabolism.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics-based discovery of XHP as a CYP3A4 inhibitor against pancreatic cancer

et al. 2023

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Background: Xihuang Wan (XHW), a purgative and detoxifying agent, is commonly utilized in modern medicine as a treatment and adjuvant therapy for various malignancies, including breast cancer, liver cancer, and lung cancer. A clinical study demonstrated the potential usefulness of the combination of XHW and gemcitabine as a therapy for pancreatic cancer (PC), indicating that XHW’s broad-spectrum antitumor herbal combination could be beneficial in the treatment of PC. However, the precise therapeutic efficacy of XHW in treating pancreatic cancer remains uncertain.Aim: This study assessed the biological activity of XHW by optimizing the therapeutic concentration of XHW (Xihuang pills, XHP). We performed cell culture and developed an animal test model to determine whether XHP can inhibit pancreatic cancer (PC). We also applied the well-known widely targeted metabolomics analysis and conducted specific experiments to assess the feasibility of our method in PC therapy.Materials and Methods: We used UPLC/Q-TOF-MS to test XHP values to set up therapeutic concentrations for the in vivo test model. SW1990 pancreatic cancer cells were cultured to check the effect the anti-cancer effects of XHP by general in vitro cell analyses including CCK-8, Hoechst 33258, and flow cytometry. To develop the animal model, a solid tumor was subcutaneously formed on a mouse model of PC and assessed by immunohistochemistry and TUNEL apoptosis assay. We also applied the widely targeted metabolomics method following Western blot and RT-PCR to evaluate multiple metabolites to check the therapeutic effect of XHP in our cancer test model.Results: Quantified analysis from UPLC/Q-TOF-MS showed the presence of the following components of XHP: 11-carbonyl-β-acetyl-boswellic acid (AKBA), 11-carbonyl-β-boswellic acid (KBA), 4-methylene-2,8,8-trimethyl-2-vinyl-bicyclo [5.2.0]nonane, and (1S-endo)-2-methyl-3-methylene-2-(4-methyl-3-3-pentenyl)-bicyclo [2.2.1heptane]. The results of the cell culture experiments demonstrated that XHP suppressed the growth of SW1990 PC cells by enhancing apoptosis. The results of the animal model tests also indicated the suppression effect of XHP on tumor growth. Furthermore, the result of the widely targeted metabolomics analysis showed that the steroid hormone biosynthesis metabolic pathway was a critical factor in the anti-PC effect of XHP in the animal model. Moreover, Western blot and RT-PCR analyses revealed XHP downregulated CYP3A4 expression as an applicable targeted therapeutic approach.Conclusion: The results of this study demonstrated the potential of XHP in therapeutic applications in PC. Moreover, the widely targeted metabolomics method revealed CYP3A4 is a potential therapeutic target of XHP in PC control. These findings provide a high level of confidence that XHP significantly acts as a CYP3A4 inhibitor in anti-cancer therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Metabolomics-based discovery of XHP as a CYP3A4 inhibitor against pancreatic cancer

et al. 2023

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“…In particular, the ability to block both PC and glutaminase by MSeA and selenite, but not by SeM, correlated well with their ability to inhibit cell proliferation and to induce ROS production. These effects of MSeA and selenite on anaplerosis led to reduced Krebs cycle activity, which in turn attenuated de novo synthesis of nucleotides and lipids, all required for supporting cell proliferation [ 93 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. We have previously shown that PC is activated in vivo in NSCLC patient tumors [ 61 ], and that both PC and glutaminolysis are important for supporting lung cancer cell proliferation [ 91 ] .…”

Section: Discussionmentioning

confidence: 99%

Differential Inhibition of Anaplerotic Pyruvate Carboxylation and Glutaminolysis-Fueled Anabolism Underlies Distinct Toxicity of Selenium Agents in Human Lung Cancer

et al. 2023

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Past chemopreventive human trials on dietary selenium supplements produced controversial outcomes. They largely employed selenomethionine (SeM)-based diets. SeM was less toxic than selenite or methylseleninic acid (MSeA) to lung cancer cells. We thus investigated the toxic action of these Se agents in two non-small cell lung cancer (NSCLC) cell lines and ex vivo organotypic cultures (OTC) of NSCLC patient lung tissues. Stable isotope-resolved metabolomics (SIRM) using 13C6-glucose and 13C5,15N2-glutamine tracers with gene knockdowns were employed to examine metabolic dysregulations associated with cell type- and treatment-dependent phenotypic changes. Inhibition of key anaplerotic processes, pyruvate carboxylation (PyC) and glutaminolysis were elicited by exposure to MSeA and selenite but not by SeM. They were accompanied by distinct anabolic dysregulation and reflected cell type-dependent changes in proliferation/death/cell cycle arrest. NSCLC OTC showed similar responses of PyC and/or glutaminolysis to the three agents, which correlated with tissue damages. Altogether, we found differential perturbations in anaplerosis-fueled anabolic pathways to underlie the distinct anti-cancer actions of the three Se agents, which could also explain the failure of SeM-based chemoprevention trials.

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“…Metabolic reprogramming, a hallmark of most types of cancer, plays a vital role in cancer cell growth, energy metabolism, storage, and signaling (7)(8)(9). Targeting genes or enzymes involved in metabolism could be a promising strategy to inhibit cancer cell growth (10,11). Previous studies have demonstrated that fatty acid metabolism, especially the desaturation process, is critical for cancer progression and therapy evasion (12,13).…”

Section: Introductionmentioning

confidence: 99%

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response

Heravi,

Liu,

Herroon

et al. 2024

Preprint

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Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1's role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

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Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy

Cited by 13 publications

References 185 publications

Metabolomics-based discovery of XHP as a CYP3A4 inhibitor against pancreatic cancer

Metabolomics-based discovery of XHP as a CYP3A4 inhibitor against pancreatic cancer

Differential Inhibition of Anaplerotic Pyruvate Carboxylation and Glutaminolysis-Fueled Anabolism Underlies Distinct Toxicity of Selenium Agents in Human Lung Cancer

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response

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