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Cited by 124Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerBioactive Compounds and Antitumor Agents

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The Potential of Lonidamine in Combination with Chemotherapy and Physical Therapy in Cancer Treatment

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Huang, Yaxin, Sun, Guohui, Sun, Xiaodong, Li, Feifan, Zhao, Lijiao, Zhong, Rugang, Peng, Yongzhen·2020·Cancers
DOI 10.3390/cancers12113332PMC PMC7696079
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Abstract

Lonidamine (LND) has the ability to resist spermatogenesis and was first used as an anti-spermatogenic agent. Later, it was found that LND has a degree of anticancer activity. Currently, LND is known to target energy metabolism, mainly involving the inhibition of monocarboxylate transporter (MCT), mitochondrial pyruvate carrier (MPC), respiratory chain complex I/II, mitochondrial permeability transition (PT) pore, and hexokinase II (HK-II). However, phase II clinical studies showed that LND alone had a weak therapeutic effect, and the effect was short and reversible. Interestingly, LND does not have the common side effects of traditional chemotherapeutic drugs, such as alopecia and myelosuppression. In addition, LND has selective activity toward various tumors, and its toxic and side effects do not overlap when combined with other chemotherapeutic drugs. Therefore, LND is commonly used as a chemosensitizer to enhance the antitumor effects of chemotherapeutic drugs based on its disruption of energy metabolism relating to chemo- or radioresistance. In this review, we summarized the combination treatments of LND with several typical chemotherapeutic drugs and several common physical therapies, such as radiotherapy (RT), hyperthermia (HT), and photodynamic therapy (PDT), and discussed the underlying mechanisms of action. Meanwhile, the development of novel formulations of LND in recent years and the research progress of LND derivative adjudin (ADD) as an anticancer drug were also discussed.

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Crossref · 10.3390/cancers12113332

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Figures

Figure 1 Molecular structures of (A) LND and (B) ADD. LND and ADD are indazole derivatives. Their chemical names are 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid and 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, respectively.
Figure 1 Molecular structures of (A) LND and (B) ADD. LND and ADD are indazole derivatives. Their chemical names are 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid and 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, respectively.CC BY · PubMed Central
Figure 2 Underlying mechanisms of LND-mediated antitumor activity. (1) LND inhibits the lactate export and the uptake of pyruvate into mitochondria by the inhibition of proton-linked monocarboxylate transporter (MCT) and mitochondrial pyruvate carrier (MPC), respectively. (2) LND inhibits complexes I and II by interfering with ubiquinone reduction, leading to ATP depletion and ROS production. (3) LND affects the mitochondrial permeability transition (PT) pore which is under the control of the members of the Bcl-2 family. (4) LND inhibits glycolysis through the inhibition of hexokinase II (HK-II), thereby reducing the levels of NADPH and glutathione (GSH) in part by the inhibition of the pentose phosphate pathway (PPP) flux.
Figure 2 Underlying mechanisms of LND-mediated antitumor activity. (1) LND inhibits the lactate export and the uptake of pyruvate into mitochondria by the inhibition of proton-linked monocarboxylate transporter (MCT) and mitochondrial pyruvate carrier (MPC), respectively. (2) LND inhibits complexes I and II by interfering with ubiquinone reduction, leading to ATP depletion and ROS production. (3) LND affects the mitochondrial permeability transition (PT) pore which is under the control of the members of the Bcl-2 family. (4) LND inhibits glycolysis through the inhibition of hexokinase II (HK-II), thereby reducing the levels of NADPH and glutathione (GSH) in part by the inhibition of the pentose phosphate pathway (PPP) flux.CC BY · PubMed Central
Figure 3 Targeting three key ways to cut off the tumor’s energy and matter supply. Cancer cells obtain energy and matter mainly through glycolysis, glutaminolysis, and fatty acid synthesis. Cutting off these three pathways can inhibit tumor growth.
Figure 3 Targeting three key ways to cut off the tumor’s energy and matter supply. Cancer cells obtain energy and matter mainly through glycolysis, glutaminolysis, and fatty acid synthesis. Cutting off these three pathways can inhibit tumor growth.CC BY · PubMed Central
Figure 4 Synergistic model of DON in combination with LND and orlistat. LND inhibits glycolysis by inhibiting hexokinase II (HK-II), DON inhibits glutaminolysis by inhibiting kidney-type glutaminase (GLS1), and Orilistat inhibits fatty acid synthesis by inhibiting the FA synthase.
Figure 4 Synergistic model of DON in combination with LND and orlistat. LND inhibits glycolysis by inhibiting hexokinase II (HK-II), DON inhibits glutaminolysis by inhibiting kidney-type glutaminase (GLS1), and Orilistat inhibits fatty acid synthesis by inhibiting the FA synthase.CC BY · PubMed Central
Figure 5 Synergistic model of the combination of ATO and LND. The combination of ATO and LND could inhibit the phosphorylation of AKT, mTOR, and ERK in the MEK/ERK and AKT/mTOR signaling pathways, respectively, and reduce cell proliferation.
Figure 5 Synergistic model of the combination of ATO and LND. The combination of ATO and LND could inhibit the phosphorylation of AKT, mTOR, and ERK in the MEK/ERK and AKT/mTOR signaling pathways, respectively, and reduce cell proliferation.CC BY · PubMed Central
Figure 6 Synergistic model of the combination of MAT and LND for the treatment of human myeloid leukemia cells. MAT can inhibit the binding of c-Myc to HK-II gene intron. When in combination with LND, it can reduce the expression of HK-II and inhibit the glycolysis.
Figure 6 Synergistic model of the combination of MAT and LND for the treatment of human myeloid leukemia cells. MAT can inhibit the binding of c-Myc to HK-II gene intron. When in combination with LND, it can reduce the expression of HK-II and inhibit the glycolysis.CC BY · PubMed Central

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Cites

Show all 119 references

Research works printed but not linked: 4

  1. Cioli, 1980, Anti-spermogenic activity of lonidamine (AF-1890) in rabbit, Ultramicroscopy, 5, 418
  2. Lin, 2011, The progress of the platinum antitumor drugs and clinical evaluation, Eval. Anal. Drug Use Hosp. China, 11, 4
  3. Yu, 2010, LND and NP regimen treament for advanced non-small cell lung cancer, Chin. Clin. Oncol., 37, 763
  4. Zhang, 2016, Research progress on the relationship between tumor microenvironment and radiosensitivity of tumor cells, J. Jilin. Univ. Med. Edit., 42, 1038

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Metadata

Authors
Huang, Y., Sun, G., Sun, X., Li, F., Zhao, L., Zhong, R., & Peng, Y.
Affiliations
Beijing University of Technology (CN)
Corresponding author
Sun, Guohui
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2020-11-11
Volume
12
Issue
11
Pages
3332
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers12113332
PMC
PMC7696079
OpenAlex
W3105923034
Cited by
124
References
119
Citations by year
2026: 15 · 2025: 32 · 2024: 25 · 2023: 27 · 2022: 15 · 2021: 10
FWCI
1.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82003599, 21778011)
  • Science and Technology General Project of Beijing Municipal Education Commission (KM202110005005)
  • Beijing Natural Science Foundation (7184192)
  • Beijing Postdoctoral Research Foundation (2018-ZZ-022, ZZ2019-30)
  • the Great Wall Scholars Program of Beijing Municipal Education Commission (CIT&TCD20180308)
  • Science and Technology Key Project of Beijing Municipal Education Commission (PXM2015_014204_500175)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords
lonidamine, adjudin, chemosensitization, cancer energy metabolism, mitochondrial pyruvate carrier, mitochondrial permeability transition pore, hexokinase 2, chemoresistance, radiosensitization, hyperthermia, photodynamic therapy, combination therapy

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