J Cancer 2013; 4(9):703-715. doi:10.7150/jca.7235

Research Paper

Simultaneous Inhibition of Cell-Cycle, Proliferation, Survival, Metastatic Pathways and Induction of Apoptosis in Breast Cancer Cells by a Phytochemical Super-Cocktail: Genes That Underpin Its Mode of Action

Allal Ouhtit1,2*, Rajiv Lochan Gaur1,3*, Mohamed Abdraboh1,4*, Shubha K. Ireland5*, Prakash N Rao6, Shailaja G Raj7, Hamad Al-Riyami2, Somya Shanmuganathan2, Ishita Gupta2, Subramanyam N Murthy8, Andrew Hollenbach9, Madhwa HG Raj1,10✉

1. Stanley S Scott Cancer Center, Louisiana Health Sciences Center, New Orleans, Louisiana.
2. Present address: Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Oman;
3. Present address: Department of Pathology, Stanford University, California.
4. Present address: Faculty of Science, University of Mansora, Egypt
5. Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana.
6. New Jersey Organ and Tissue Sharing Network, New Jersey.
7. Protegene Corporation, Metairie, Louisiana.
8. Departnent of Environmental Toxicology, Southern University and A & M College, Baton Rouge, Louisiana,
9. Department of Genetics, LSU Health Sciences Center, New Orleans, Louisiana, USA,
10. Department of Obstetrics & Gynecology, Louisiana Health Sciences Center.
* These four authors equally contributed to this work.

Abstract

Traditional chemotherapy and radiotherapy for cancer treatment face serious challenges such as drug resistance and toxic side effects. Complementary / Alternative medicine is increasingly being practiced worldwide due to its safety beneficial therapeutic effects. We hypothesized that a super combination (SC) of known phytochemicals used at bioavailable levels could induce 100% killing of breast cancer (BC) cells without toxic effects on normal cells and that microarray analysis would identify potential genes for targeted therapy of BC. Mesenchymal Stems cells (MSC, control) and two BC cell lines were treated with six well established pro-apoptotic phytochemicals individually and in combination (super cocktail), at bioavailable levels. The compounds were ineffective individually. In combination, they significantly suppressed BC cell proliferation (>80%), inhibited migration and invasion, caused cell cycle arrest and induced apoptosis resulting in 100% cell death. However, there were no deleterious effects on MSC cells used as control. Furthermore, the SC down-regulated the expression of PCNA, Rb, CDK4, BcL-2, SVV, and CD44 (metastasis inducing stem cell factor) in the BC cell lines. Microarray analysis revealed several differentially expressed key genes (PCNA, Rb, CDK4, Bcl-2, SVV, P53 and CD44) underpinning SC-promoted BC cell death and motility. Four unique genes were highly up-regulated (ARC, GADD45B, MYLIP and CDKN1C). This investigation indicates the potential for development of a highly effective phytochemical combination for breast cancer chemoprevention / chemotherapy. The novel over-expressed genes hold the potential for development as markers to follow efficacy of therapy.

Keywords: Breast cancer, phytochemicals, chemoprevention, microarray, metastasis

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How to cite this article:
Ouhtit A, Gaur RL, Abdraboh M, Ireland SK, Rao PN, Raj SG, Al-Riyami H, Shanmuganathan S, Gupta I, Murthy SN, Hollenbach A, Raj MH. Simultaneous Inhibition of Cell-Cycle, Proliferation, Survival, Metastatic Pathways and Induction of Apoptosis in Breast Cancer Cells by a Phytochemical Super-Cocktail: Genes That Underpin Its Mode of Action. J Cancer 2013; 4(9):703-715. doi:10.7150/jca.7235. Available from http://www.jcancer.org/v04p0703.htm