Enhancement of apoptotic activities on brain cancer cells via the combination of γ-tocotrienol and jerantinine A.

Abstract

BACKGROUND:

γ-Tocotrienol, a vitamin E isomer possesses pronounced in vitro anticancer activities. However, the in vivo potency has been limited by hardly achievable therapeutic levels owing to inefficient high-dose oral delivery which leads to subsequent metabolic degradation. Jerantinine A, an Aspidosperma alkaloid, originally isolated from Tabernaemontana corymbosa, has proved to possess interesting anticancer activities. However, jerantinine A also induces toxicity to non-cancerous cells.

PURPOSE:

We adopted a combinatorial approach with the joint application of γ-tocotrienol and jerantinine A at lower concentrations in order to minimize toxicity towards non-cancerous cells while improving the potency on brain cancer cells.

METHODS:

The antiproliferative potency of individual γ-tocotrienol and jerantinine A as well as combined in low-concentration was firstly evaluated on U87MG cancer and MRC5 normal cells. Morphological changes, DNA damage patterns, cell cycle arrests and the effects of individual and combined low-concentration compounds on microtubules were then investigated. Finally, the potential roles of caspase enzymes and apoptosis-related proteins in mediating the apoptotic mechanisms were investigated using apoptosis antibody array, ELISA and Western blotting analysis.

RESULTS:

Combinatorial study between γ-tocotrienol at a concentration range (0-24µg/ml) and fixed IC20 concentration of jerantinine A (0.16µg/ml) induced a potent antiproliferative effect on U87MG cells and led to a reduction on the new half maximal inhibitory concentration of γ-tocotrienol (i.e.tIC50=1.29µg/ml) as compared to that of individual γ-tocotrienol (i.e. IC50=3.17µg/ml). A reduction on undesirable toxicity to MRC5 normal cells was also observed. G0/G1 cell cycle arrest was evident on U87MG cells receiving IC50 of individual γ-tocotrienol and combined low-concentration compounds (1.29µg/ml γ-tocotrienol + 0.16µg/ml jerantinine A), whereas, a profound G2/M arrest was evident on cells treated with IC50 of individual jerantinine A. Additionally, individual jerantinine A and combined compounds (except individual γ-tocotrienol) caused a disruption of microtubule networks triggering Fas- and p53-induced apoptosis mediated via the death receptor and mitochondrial pathways.

CONCLUSIONS:

These findings demonstrated that the combined use of lower concentrations of γ-tocotrienol and jerantinine A induced potent cytotoxic effects on U87MG cancer cells resulting in a reduction on the required individual concentrations and thereby minimizing toxicity of jerantinine A towards non-cancerous MRC5 cells as well as probably overcoming the high-dose limiting application of γ-tocotrienol. The multi-targeted mechanisms of action of the combination approach have shown a therapeutic potential against brain cancer in vitro and therefore, further in vivo investigations using a suitable animal model should be the way forward.

• Authors: Ibrahim Babangida Abubakar, Kuan-Hon Lim, Toh-Seok Kam, Hwei-San Loh
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 30 Pg. 74-84 (Jul 01 2017) ISSN: 1618-095X [Electronic] Germany
• PMID: 28545672 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier GmbH. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Apoptosis Regulatory Proteins
• Chromans
• Indole Alkaloids
• jerantinine A
• Vitamin E
• plastochromanol 8
• Caspases

Topics

• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromans (administration & dosage, adverse effects)
• Drug Screening Assays, Antitumor (methods)
• Humans
• Indole Alkaloids (administration & dosage)
• Inhibitory Concentration 50
• Mitochondria (drug effects, metabolism)
• Vitamin E (administration & dosage, adverse effects, analogs & derivatives)