Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

Hoshiko, Toshimi; Kubota, Yasushi; Onodera, Risako; Higashi, Taishi; Yokoo, Masako; Motoyama, Keiichi; Kimura, Shinya

doi:10.3390/cancers13215413

Cited by 9 publications

(11 citation statements)

References 40 publications

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“…Interestingly, the analogue of cucurbiturils (molecules forming complexes according to the guest-host type)–cyclodextrin and calixarenes have not cytotoxic activity against the K562 tumor line as also cucurbituril. However, complex formation or modification of the nanosubstance’s structure increases their antitumor activity in regard chronic myeloid leukemia [ 46 , 47 ]. Increased antitumor activity was associated with apoptosis of these cells, but it is not clear whether this is due to the generation of reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Influence of Cucurbiturils on the Production of Reactive Oxygen Species by T- and B-Lymphocytes, Platelets and Red Blood Cells

Aktanova

Boeva

Barkovskaya

et al. 2023

IJMS

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Reactive oxygen species (ROS) are highly reactive chemical molecules containing oxygen. ROS play an important role in signaling and cell homeostasis at low and moderate concentrations. ROS could be a cause of damage to proteins, nucleic acids, lipids, membranes and organelles at high concentrations. There are a lot of cells that can produce ROS to maintain functional activity. It is known that metal nanoparticles can increase production of ROS in cells. However, the effect of cucurbiturils on ROS production is still unknown. In our study, we evaluated production of ROS by the immune (T-, B-lymphocytes, NK-cells) and non-immune cells (red blood cells, platelets), as well as tumor cells line (1301, K562) after treatment with cucurbiturils in vitro. Assessment of reactive oxide species (ROS) were provided by using dihydrorhodamine 123 (DHR 123). Fluorescence intensity and percentage DHR123 were measured by flow cytometry. Platelets, erythrocytes and activated T-helpers were changed the level of ROS production in response to stimulation with cucurbiturils. It was found that the percentage of these ROS-producing cells was reduced by cucurbiturils. Thus, cucurbiturils may affect the production of ROS by cells, but further research is needed in this area.

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Section: Discussionmentioning

confidence: 99%

Influence of Cucurbiturils on the Production of Reactive Oxygen Species by T- and B-Lymphocytes, Platelets and Red Blood Cells

Aktanova

Boeva

Barkovskaya

et al. 2023

IJMS

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“…Substitution of hydroxypropyl cyclodextrin with a folate group as described for the materials above could be performed to provide a material with the capability to cause autophagic cell death in chronic myeloid leukemia cells, especially when combined with imatinib, an ABL tyrosine kinase inhibitor [89]. In mouse models, this combined therapy had a much stronger inhibitory effect on cancer progression than either component separately.…”

Section: Medical Applicationsmentioning

confidence: 99%

Synthetic Receptors for Early Detection and Treatment of Cancer

Davis,

Higson

2023

Biosensors

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Over recent decades, synthetic macrocyclic compounds have attracted interest from the scientific community due to their ability to selectively and reversibly form complexes with a huge variety of guest moieties. These molecules have been studied within a wide range of sensing and other fields. Within this review, we will give an overview of the most common synthetic macrocyclic compounds including cyclodextrins, calixarenes, calixresorcinarenes, pillarenes and cucurbiturils. These species all display the ability to form a wide range of complexes. This makes these compounds suitable in the field of cancer detection since they can bind to either cancer cell surfaces or indeed to marker compounds for a wide variety of cancers. The formation of such complexes allows sensitive and selective detection and quantification of such guests. Many of these compounds also show potential for the detection and encapsulation of environmental carcinogens. Furthermore, many anti-cancer drugs, although effective in in vitro tests, are not suitable for use directly for cancer treatment due to low solubility, inherent instability in in vivo environments or an inability to be adsorbed by or transported to the required sites for treatment. The reversible encapsulation of these species in a macrocyclic compound can greatly improve their solubility, stability and transport to required sites where they can be released for maximum therapeutic effect. Within this review, we intend to present the use of these species both in cancer sensing and treatment. The various macrocyclic compound families will be described, along with brief descriptions of their synthesis and properties, with an outline of their use in cancer detection and usage as therapeutic agents. Their use in the sensing of environmental carcinogens as well as their potential utilisation in the clean-up of some of these species will also be discussed.

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“…The IC 50 values of Ara-C for HL-60, THP1 and SKM1 cells were 0.495 µM, 7.19 µM and 0.6 µM, respectively, and those of Venetoclax were 50.3 nM, 441.8 nM and 1.1 µM, respectively. The combination index (CI) and Fa values for each dilution were calculated using CalcuSyn software (version 1.1.1), as reported previously (Figures S8-S10) [22,33]. Dose-effect and CI-Fa plots illustrating the effect of the combinations of FA-HP-β-CyD and Ara-C or Venetoclax are presented in Figure 6.…”

Section: Fa-hp-β-cyd Acts Synergistically To Enhance the Effects Of A...mentioning

confidence: 99%

“…Previously, we showed that HP-β-CyD exerts antitumor activity against BCR-ABL-positive cells, but its lack of tumor cell selectivity raised concerns about systemic cytotoxicity [21]. Therefore, we synthesized folate-appended HP-β-CyD (FA-HPβ-CyD) [22] to increase tumor cell selectivity (folate receptors (FRs) are highly expressed by tumor cells) [23,24], and showed that FA-HP-β-CyD was not toxic to FR-negative cells; however, it induced both apoptosis and autophagic cell death in chronic myeloid leukemia (CML) cells [22].…”

Section: Introductionmentioning

confidence: 99%

Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells

Kubota,

Hoshiko,

Higashi

et al. 2023

IJMS

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Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-β-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-β-CyD (FA-HP-β-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-β-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-β-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-β-CyD against AML cells was stronger than that of HP-β-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-β-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-β-CyD suppressed the proliferation of AML cells in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double-deficient mice with AML. These results suggest that FA-HP-β-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy.

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Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

Cited by 9 publications

References 40 publications

Influence of Cucurbiturils on the Production of Reactive Oxygen Species by T- and B-Lymphocytes, Platelets and Red Blood Cells

Influence of Cucurbiturils on the Production of Reactive Oxygen Species by T- and B-Lymphocytes, Platelets and Red Blood Cells

Synthetic Receptors for Early Detection and Treatment of Cancer

Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells

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