Synthetic α‐mangostin dilaurate strongly suppresses wide‐spectrum organ metastasis in a mouse model of mammary cancer

Shibata, Masa‐Aki; Hamaoka, Hitomi; Morimoto, Junji; Kanayama, Tadashi; Maemura, Kentaro; Ito, Yuko; Iinuma, Munekazu; Kondo, Yoichi

doi:10.1111/cas.13590

Cited by 8 publications

(12 citation statements)

References 37 publications

(73 reference statements)

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“…In the future, in order to enhance the efficacy of α-mangostin and apigenin as chemotherapeutic agents for ovarian cancer, other application approaches could be applied, such as with fatty acid-conjugated compounds (41), or the synergistic inhibition induced by co-administration with other promising compounds (42). Moreover, the toxicity of these compounds in an in vivo model system, such as the rat, should be determined (43,44).…”

Section: Discussionmentioning

confidence: 99%

α-Mangostin and Apigenin Induced Cell Cycle Arrest and Programmed Cell Death in SKOV-3 Ovarian Cancer Cells

et al. 2019

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Ovarian cancer is the fifth main cause of pre-senescent death in women. Although chemotherapy is generally an efficient treatment, its side effects and the occurrence of chemotherapeutic resistance have prompted the need for alternative treatments. In this study, α-mangostin and apigenin were evaluated as possible anticancer alternatives to the chemotherapeutic drug doxorubicin, used herein as a positive control. The ovarian adenocarcinoma cell line SKOV-3 (ATCC No. HTB77) was used as model ovarian cancer cells, whereas the skin fibroblast line CCD-986Sk (ATCC No. CRL-1947) and lung fibroblast line WI-38 (ATCC No. CCL-75) were used as model untransformed cells. Apigenin and doxorubicin inhibited the growth of SKOV-3 cells in a dose- and time-dependent manner. After 72 hr exposure, doxorubicin was mostly toxic to SKOV-3 cells, whereas apigenin was toxic to SKOV-3 cells but not CCD-986Sk and WI-38 cells. α-Mangostin was more toxic to SKOV-3 cells than to CCD-986Sk cells. A lower cell density, cell shrinkage, and more unattached (floating round) cells were observed in all treated SKOV-3 cells, but the greatest effects were observed with α-mangostin. With regard to programmed cell death, apigenin caused early apoptosis within 24 hr, whereas α-mangostin and doxorubicin caused late apoptosis and necrosis after 72 hr of exposure. Caspase-3 activity was significantly increased in α-mangostin-treated SKOV-3 cells after 12 hr of exposure, whereas only caspase-9 activity was significantly increased in apigenin-treated SKOV-3 cells at 24 hr. Both α-mangostin and apigenin arrested the cell cycle at the G 2 /M phase, but after 24 and 48 hr, respectively. Significant upregulation of BCL2 (apoptosis-associated gene) and COX2 (inflammation-associated gene) transcripts was observed in apigenin- and α-mangostin-treated SKOV-3 cells, respectively. α-Mangostin and apigenin are therefore alternative options for SKOV-3 cell inhibition, with apigenin causing rapid early apoptosis related to the intrinsic apoptotic pathway, and α-mangostin likely being involved with inflammation.

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Section: Discussionmentioning

confidence: 99%

α-Mangostin and Apigenin Induced Cell Cycle Arrest and Programmed Cell Death in SKOV-3 Ovarian Cancer Cells

et al. 2019

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“…Mice were kept for 3, 5, or 8 weeks, either under normal or irregular light/dark cycle conditions. Transplanted tumor size was measured with a caliper once a week, and volume was calculated using the following formula: tumor volume = maximum diameter (mm) × (minimum diameter (mm)) 2 × 0.4 [ 35 ]. The endpoint for tumor size defined a maximum diameter of 20 mm.…”

Section: Methodsmentioning

confidence: 99%

Metastasis of Breast Cancer Promoted by Circadian Rhythm Disruption due to Light/Dark Shift and its Prevention by Dietary Quercetin in Mice

Numata

Hirano

Yamamoto

et al. 2021

J Circadian Rhythms

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Epidemiological studies have indicated that a disturbed circadian rhythm resulting from night-shift work is a potential risk factor for breast cancer. However, the mechanism of increased risk of breast cancer by night-shift work remains unclear, and there have been few in vivo studies conducted to definitively associate the two factors. In this study, BJMC3879Luc2 mouse breast cancer cells were transplanted into BALB/c mice. Mice were maintained under lighting conditions that modeled the two-shift system and were investigated for the effect of light/dark cycle disruption on tumor growth and lymph node metastasis. Circadian dysfunction, which was confirmed by measuring circadian locomotor activities using a nano tag device in our light/dark shift model, did not affect tumor growth. However, a significant increase in the number of lymph nodes with distant metastasis was observed. Neutrophil-to-lymphocyte ratio, which is an adverse prognostic factor of breast cancer and also indicator of inflammation, also increased. It has been demonstrated that a chronic inflammatory response is associated with cancer malignancy and poor prognosis in various cancers. These results suggest that night-shift work may also affect distant metastasis and prognosis. In addition, we investigated whether dietary quercetin has anti-metastatic activity against light/dark shift-induced metastasis. A diet containing 0.3 % quercetin significantly inhibited distant lymph node metastasis, particularly metastasis to the iliac and kidney lymph nodes. Our results contribute to our understandings of the effects of the external light environment on breast cancer metastasis and provide a glimpse into potential protective effects of dietary quercetin on light/dark disturbance-induced metastasis.

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“…29 Mammary carcinomas induced by BJMC3879Luc2 inoculation have a mutant p53 protein. 27 BJMC3879Luc2 cells used in this study were maintained in Dulbecco's modified Eagle's medium with 10% FBS and penicillin-streptomycin and grown at 37°C in an incubator containing 5% CO 2 in air.…”

Section: Cell Line and Animalsmentioning

confidence: 99%

“…FFPE primary tumor tissues were analyzed using real-time RT-PCR. 27 Total RNA was extracted from FFPE tumor samples using the RNeasy FFPE Kit (Qiagen, GmbH) and cDNAs were synthesized using a Primer Script RT Reagent Kit with gDNA Eraser (Takara Bio). We subsequently amplified the resulting cDNAs using a Thermal Cycler Dice Realtime System (Takara Bio) and SYBR Premix Ex TaqII (TaKaRa Bio).…”

Section: Real-time Rt-pcr Analysismentioning

confidence: 99%

Soluble Vegfr3 gene therapy suppresses multi‐organ metastasis in a mouse mammary cancer model

Shibata

Tanaka

et al. 2020

Cancer Science

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Accumulating evidence on the association of VEGF‐C with lymphangiogenesis and lymph node metastasis implicates lymphatic vessels as a potential target in anti‐cancer therapy. To evaluate whether blocking VEGF‐C and VEGFR‐3 signaling can inhibit multi‐organ metastases, a mouse metastatic mammary cancer model was subjected to gene therapy using a soluble VEGFR‐3 expression vector (psVEGFR‐3). We showed that psVEGFR‐3 significantly diminished cell growth in vitro with or without added VEGF‐C, and significantly reduced primary tumor growth and tumor metastases to wide‐spectrum organs in vivo. Although apoptotic cell death and angiogenesis levels did not differ between the control and psVEGFR‐3 groups, cell proliferation and lymphangiogenesis in the mammary tumors were significantly decreased in the psVEGFR‐3 group. Furthermore, lymphatic vessel invasion was significantly inhibited in this group. Real‐time RT‐PCR analysis revealed significantly high expression of the Vegfr3 gene due to gene therapy, and the transcriptional levels of Pcna and Lyve1 tended to decrease in the psVEGFR‐3 group. Immunofluorescence staining indicated that phospho‐tyrosine expression was considerably lower in tumor cells of psVEGFR‐3‐treated mammary carcinomas than those of control tumors. Double immunofluorescence staining indicated that phospho‐tyrosine+/LYVE‐1+ (a lymphatic vessel marker) tended to decrease in psVEGFR‐3‐treated mammary carcinomas compared with control mice, indicating a decline in the activity of the VEGF‐C/VEGFR‐3 axis. These findings showed that a blockade of VEGF‐C/VEGFR‐3 signaling caused by sVEGFR‐3 sequestered VEGF‐C and prevented the side‐effects of anti‐angiogenesis and suppressed overall metastases, suggesting their high clinical significance.

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Synthetic α‐mangostin dilaurate strongly suppresses wide‐spectrum organ metastasis in a mouse model of mammary cancer

Cited by 8 publications

References 37 publications

α-Mangostin and Apigenin Induced Cell Cycle Arrest and Programmed Cell Death in SKOV-3 Ovarian Cancer Cells

α-Mangostin and Apigenin Induced Cell Cycle Arrest and Programmed Cell Death in SKOV-3 Ovarian Cancer Cells

Metastasis of Breast Cancer Promoted by Circadian Rhythm Disruption due to Light/Dark Shift and its Prevention by Dietary Quercetin in Mice

Soluble Vegfr3 gene therapy suppresses multi‐organ metastasis in a mouse mammary cancer model

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