Co-delivery of doxorubicin, docosahexaenoic acid, and α-tocopherol succinate by nanostructured lipid carriers has a synergistic effect to enhance antitumor activity and reduce toxicity

Eduardo Burgarelli Lages, Renata Salgado Fernandes, Juliana de Oliveira Silva, Ângelo Malachias de Souza, Geovanni Dantas Cassali, André Luís Branco de Barros, Lucas Antônio Miranda Ferreira

Biomed Pharmacother . 2020 Oct 24;132:110876. doi: 10.1016/j.biopha.2020.110876. Online ahead of print.

Abstract

Doxorubicin (DOX) is widely used in cancer treatment, however, its use is often limited due to its side effects. To avoid these shortcomings, the encapsulation of DOX into nanocarriers has been suggested. Herein, we proposed a novel nanostructured lipid carrier (NLC) formulation loading DOX, docosahexaenoic acid (DHA), and α-tocopherol succinate (TS) for cancer treatment. DHA is an omega-3 fatty acid and TS is a vitamin E derivative. It has been proposed that these compounds can enhance the antitumor activity of chemotherapeutics. Thus, we hypothesized that the combination of DOX, DHA, and TS in NLC (NLC-DHA-DOX-TS) could increase antitumor efficacy and also reduce toxicity. NLC-DHA-DOX-TS was prepared using emulsification-ultrasound. DOX was incorporated after preparing the NLC, which prevented its degradation during manufacture. High DOX encapsulation efficiency was obtained due to the ion-pairing with TS. This ion-pairing increases lipophilicity of DOX and reduces its crystallinity, contributing to its encapsulation in the lipid matrix. Controlled DOX release from the NLC was observed in vitro, with increased drug release at the acidic environment. In vitro cell studies indicated that DOX, DHA, and TS have synergistic effects against 4T1 tumor cells. The in vivo study showed that NLC-DHA-DOX-TS exhibited the greatest antitumor efficacy by reducing tumor growth in 4T1 tumor-bearing mice. In addition, this formulation reduced mice mortality, prevented lung metastasis, and decreased DOX-induced toxicity to the heart and liver, which was demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that NLC-DHA-DOX-TS may be a promising carrier for breast cancer treatment.

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Chemical Pathology of Homocysteine VIII. Effects of Tocotrienol, Geranylgeraniol, and Squalene on Thioretinaco Ozonide, Mitochondrial Permeability, and Oxidative Phosphorylation in Arteriosclerosis, Cancer, Neurodegeneration and Aging

Kilmer S McCully

Ann Clin Lab Sci . 2020 Sep;50(5):567-577.

Abstract

A century ago a fat-soluble vitamin from leafy vegetables, later named vitamin E, was discovered to enhance fertility in animals. Vitamin E consists of 8 isomers of tocopherols and tocotrienols, each containing chromanol groups that confer antioxidant properties and differ only in the 15-carbon saturated phytyl poly-isoprenoid side chain of tocopherols and the 15-carbon unsaturated farnesyl poly-isoprenoid side chain of tocotrienols. Although tocotrienol was first isolated from rubber plants in 1964, its importance in multiple disease processes was not recognized until two decades later, when the cholesterol-lowering and anti-cancer effects were first reported. Tocotrienol (T3) protects against radiation injury and mitochondrial dysfunction by preventing opening of the mitochondrial permeability transition pore, thereby inhibiting loss of the active site for oxidative phosphorylation, thioretinaco ozonide oxygen ATP, from mitochondria by complex formation with the active site, TR2CoO3O2NAD+H2PO4 T3. The preventive effects of tocotrienol on vascular disease, cancer, neurodegeneration and aging are attributed to its effects on cellular apoptosis and senescence. Geranylgeraniol is an important intermediate in the biosynthesis of cholesterol, and cholesterol auxotrophy of lymphoma cell lines and primary tumors is attributed to loss of squalene monooxygenase and accumulation of intracellular squalene. Geranylgeraniol and tocotrienol have synergistic inhibitory effects on growth and HMG CoA reductase activity, accompanied by reduction of membrane KRAS protein of cultured human prostate carcinoma cells. Since cholesterol inhibits opening of the mPTP pore of mitochondria, inhibition of cholesterol biosynthesis by these effects of tocotrienol and geranylgeraniol produces increased mitochondrial dysfunction and apoptosis from loss of the active site of oxidative phosphorylation from mitochondria.

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Gamma-Tocotrienol loaded liposomes as radioprotection from hematopoietic side effects caused by radiotherapeutic drugs

Sang-Gyu Lee, Teja Muralidhar Kalidindi, Hanzhi Lou, Kishore Gangangari, Blesida Punzalan, Ariana Bitton 2, Casey Lee, Soobin Park, Lisa Bodei, Michael Kharas, Vijay K Singh, NagaVaraKishore Pillarsetty, Steven M Larson

J Nucl Med . 2020 Aug 21;jnumed.120.244681. doi: 10.2967/jnumed.120.244681. Online ahead of print.

Abstract

Rationale: With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of gamma-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy (TRT). Methods: GT3 was loaded into liposomes using passive loading. [64Cu]-GT3-Nano and 3H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. Radioprotection efficacy of GT3-Nano was assessed after acute 137Cs whole-body irradiation at sublethal (4 Gy), lethal (9 Gy), or single high-dose [153Sm]-EDTMP administration. Flow cytometry was used to analyze hematopoietic cell population dynamics and fluorescence microscopy was used to assess the cellular site of GT3-Nano localization in the spleen and bone marrow. Results: Bone marrow uptake and retention of [64Cu]-GT3-Nano was 6.98 ± 2.34 %ID/g, while [3H]-GT3-Nano uptake and retention was 7.44 ± 2.52 %ID/g at 24 h, respectively. GT3-Nano administered 24 hours before or after 4 Gy TBI promoted rapid and complete hematopoietic recovery while recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9 Gy TBI. Flow cytometry of bone marrow indicated progenitor bone marrow cells MPP2 and CMP cells were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. Conclusion: GT3-Nano is highly effective in mitigating marrow suppressive effects of sub-lethal and lethal TBI in mice. GT3-Nano can aid in rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent [153Sm]-EDTMP.

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The wonders of palm oil

Ahmad Parveez Ghulam Kadir

The Malaysian Palm Oil Board (MPOB)’s research and collaborations with local and overseas institutions have scientifically proven that palm-derived Vitamin E tocotrienols are important for human health as they can prevent many non-communicable diseases. Through the continuous and dedicated research conducted by MPOB, the health benefits of palm oil and its phyto-nutrients are being explored extensively.

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Synergistic Impact of Xanthorrhizol and d-δ-Tocotrienol on the Proliferation of Murine B16 Melanoma Cells and Human DU145 Prostate Carcinoma Cells

Darren Chan, Maureen L Meister, Chappell R Madhani, Manal Elfakhani, Sophie T Yount, Xiangming Ji, Rafaela G Feresin, Desiree Wanders, Huanbiao Mo

Nutr Cancer . 2020 Aug 18;1-12. doi: 10.1080/01635581.2020.1807573. Online ahead of print

Abstract

Isoprenoids suppress the mevalonate pathway that provides prenyl groups for the posttranslational modification of growth-regulating proteins. We hypothesize that xanthorrhizol and d-δ-tocotrienol synergistically suppress the growth of murine B16 melanoma and human DU145 prostate carcinoma cells. Xanthorrhizol (0-200 µmol/L; half maximal inhibitory concentration [IC50] = 65 µmol/L) and d-δ-tocotrienol (0-40 µmol/L; IC50 = 20 µmol/L) each induced a concentration-dependent suppression of the proliferation of B16 cells and concurrent cell cycle arrest at the G1 phase. A blend of 16.25 µmol/L xanthorrhizol and 10 µmol/L d-δ-tocotrienol suppressed B16 cell proliferation by 69%, an impact greater than the sum of those induced by xanthorrhizol (15%) and d-δ-tocotrienol (12%) individually. The blend cumulatively reduced the levels of cyclin-dependent kinase four and cyclin D1, key regulators of cell cycle progression at the G1 phase. The expression of RAS and extracellular signal-regulated kinase (ERK1/2) in the proliferation-stimulating RAS-RAF-MEK-ERK pathway was downregulated by the blend. Xanthorrhizol also induced a concentration-dependent suppression of the proliferation of DU145 cells with concomitant morphological changes. Isobologram confirmed the synergistic effect of xanthorrhizol and d-δ-tocotrienol on DU145 cell proliferation with combination index values ranging 0.61-0.94. Novel combinations of isoprenoids with synergistic actions may offer effective approaches in cancer prevention and therapy.

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Primary and Secondary Markers of Doxorubicin-Induced Female Infertility and the Alleviative Properties of Quercetin and Vitamin E in a Rat Model

Mohammad Samare-Najaf, Fatemeh Zal, Solmaz Safari

Reprod Toxicol . 2020 Aug 15;96:316-326. doi: 10.1016/j.reprotox.2020.07.015. Online ahead of print.

Abstract

The incidence of cancer has recently risen among the women at the reproductive age. Therefore, exposure to doxorubicin (DOX) chemotherapy has become a cause of reproductive toxicity followed by secondary destructive effects. The present study aimed to evaluate the effects of quercetin (QCT) and vitamin.E (Vit.E) on doxorubicin-induced toxicity in the ovary and uterus, and the secondary bone-related effects in a rat model. Animals were divided into six groups including control normal saline/corn oil (CON), QCT at 20 mg/Kg, Vit.E at 200 mg/Kg, DOX at accumulative 15 mg/Kg, DOX/QCT, and DOX/Vit.E. After 21 days of treatment, the alterations were analyzed in histoarchitecture, apoptosis, hormones secretion, the gene expression of aromatase and estrogen α-receptor (ER-α) in the uterine and ovarian tissues, and serum levels of bone-related factors. The results demonstrated the ameliorative effects of QCT and Vit.E on doxorubicin caused altered ovarian histology, increased apoptosis, decreased ovarian aromatase and ER-α gene expression (p-value<0.05), decreased estrogen and progesterone levels, decreased ALP (p-value<0.001), and increased osteocalcin (p-value<0.05). The findings suggested that the studied antioxidants administration could be a promising fertility preservation strategy in DOX-treated females.

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A review on vitamin E natural analogues and on the design of synthetic vitamin E derivatives as cytoprotective agents

Panagiotis Theodosis-Nobelos, Georgios Papagiouvannis, Eleni A Rekka

Mini Rev Med Chem . 2020 Aug 7. doi: 10.2174/1389557520666200807132617. Online ahead of print.

Abstract

Vitamin E, essential for human health, is widely used worldwide for therapeutic or dietary reasons. The differences in the metabolism and excretion of the multiple vitamin E forms are presented in this review. The important steps that influence the kinetics of each form and the distribution and processing of vitamin E forms by the liver are considered. The antioxidant as well as non-antioxidant properties of vitamin E forms are discussed. Finally, synthetic tocopherol and trolox derivatives, based on the design of multitarget directed compounds, are reviewed. It is demonstrated that selected derivatization of vitamin E or trolox structures can produce improved antioxidants, agents against cancer, cardiovascular and neurodegenerative disorders.

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Update on the Anti-Cancer Potency of Tocotrienols and α-Tocopheryl Polyethylene Glycol 1000 Succinate on Leukemic Cell Lines

Constantina Constantinou, Christiana Charalambous, Dimitrios Kanakis, Ourania Kolokotroni, Andreas I Constantinou

Nutr Cancer . 2020 Jul 22;1-7. doi: 10.1080/01635581.2020.1797128. Online ahead of print.

Abstract

The natural isoforms of vitamin E γ-tocotrienol (γ-ΤΤ) and δ-tocotrienol (δ-ΤΤ) and the synthetic derivative α-tocopheryl polyethylene glycol 1000 succinate (TPGS) have promising anticancer potency in a variety of cancer cell lines and animal models of cancer. Ongoing clinical trials are investigating the anti-tumor effectiveness of TTs in combination with chemotherapeutic agents in patients suffering from breast, colon, non-small cell lung and ovarian cancers. Despite extensive research on different types of cancer, the anticancer potency of TTs and TPGS has not been thoroughly investigated in leukemias. Given the fact that certain types of leukemias have very low survival rates and that patients suffer significantly from the toxic side effects of chemotherapeutic drugs, there is a need to develop novel treatments with increased specificity against cancer cells and reduced toxicity to the patients. The aim of this review is to report current evidence on the anticancer potency of TTs and TPGS on leukemic cells lines and to discuss future studies that could be carried out to investigate the role of these agents in the management of leukemias.

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Acylphloroglucinol and tocotrienol derivatives from the fruits of Garcinia paucinervis

Xue Tan, Fangfang Zhong, Hongli Teng, Qingqing Li, Yitong Li, Zhinan Mei, Yu Chen, Guangzhong Yang

Fitoterapia . 2020 Jul 21;146:104688. doi: 10.1016/j.fitote.2020.104688. Online ahead of print.

Abstract

Three undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) and three tocotrienols derivatives, named as paucinochymol A-F (1-3 and 10-12), together with six known PPAPs, were isolated from the fruits of Garcinia paucinervis. Their structures and absolute configurations were determined by extensive NMR analysis and electronic circular dichroism (ECD) calculation methods. Paucinochymol A (1) is the first compound of this type featuring a ω-isogeranyl with tetrahydrofuran unit at C-1. Paucinochymols D and E (4-5) belong to rare tocotrienol with one glorious macrocyclic and an ortho-quinone moiety, respectively. The antiproliferative and anti-inflammatory activities of all isolates were tested. Four PPAPs exhibited weak inhibitory activities against three human cancer cell lines (HepG2, T98, MCF-7) with IC50 values ranging from 10.0 to 16.0 μM. Paucinochymol D (10) displayed moderate inhibitory effects against nitric oxide (NO) production with the IC50 value of 19.8 μM.

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Stereological and histopathological evaluation of doxorubicin-induced toxicity in female rats’ ovary and uterus and palliative effects of quercetin and vitamin E

M Samare-Najaf, F Zal, S Safari, F Koohpeyma, N Jamali

Hum Exp Toxicol . 2020 Jul 15;960327120937329. doi: 10.1177/0960327120937329. Online ahead of print

Abstract

Doxorubicin (DOX) is a widely used chemotherapeutic agent with demonstrated reproductive toxicity. This study sought to determine the DOX-induced toxicity in the ovary and uterus and the preventive effects of quercetin (QCT) and vitamin E (Vit.E). Female rats were divided into six groups as follows: control, QCT (20 mg/kg), Vit.E (200 mg/kg), DOX (accumulative 15 mg/kg), DOX/QCT, and DOX/Vit.E. After 3 weeks, the toxicity of DOX in ovarian and uterine tissues and the potential palliative effects of QCT and Vit.E were evaluated by histopathological-stereological methods. The findings indicate a dramatic decline in the number of ovarian follicles (p < 0.001), ovarian and its associated structures volume, the volume of the uterus, its layers, and related structures (p < 0.05). Coadministration of QCT and Vit.E with DOX-treated rats demonstrated an alleviative effect on most of the studied parameters. Nevertheless, few adverse effects were recognized concerning these antioxidants administration (p < 0.05). In conclusion, the findings of this study support the protective role of these dietary supplements in the prevention of DOX-induced toxicity in uterine and ovarian tissues.

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