Effect of a nutrient mixture on the localization of extracellular matrix proteins in HeLa human cervical cancer xenografts in female nude mice

Abstract

Abstract. Cervical cancer is one of the most commonly diagnosed cancers and a significant cause of mortality in women worldwide. Although cervical cancer is fully treatable in the early stages, once it has metastasized, patient outcome is poor. The objective of the present study was to investigate the effect of dietary supplementation with a nutrient mixture (NM) containing lysine, ascorbic acid, proline, green tea extract and other micronutrients on the expression of extracellular matrix (ECM) proteins in HeLa cell xenografts in nude female mice. After housing for 1 week, female athymic nude mice between 5 and 6 weeks of age (n=12) were inoculated subcutaneously with 3x106 HeLa cells in phosphate-buffered saline and Matrigel and randomly divided into two groups. These were the control group, in which the mice were fed with regular mouse chow, and the NM group, in which the mice were fed with the regular diet supplemented with 0.5% NM (w/w). After 4 weeks, the tumors were excised and processed for histology. Tumor growth was evaluated and the tumors were stained for the ECM proteins collagen I, collagen IV, fibronectin, laminin, periodic acid-Schiff (PAS) and elastin. NM strongly inhibited (by 59%, P=0.001) the growth of HeLa xenografts in nude mice. Tumors from control mice exhibited little to no collagen I expression either internally or in the fibrous capsule, while tumors from the NM group expressed collagen I in the fibrous capsule and within the tumor. Tumors from the control group showed diffuse cytoplasmic and capsular collagen IV with abundant nucleated cells. NM treatment substantially increased collagen IV production and induced a dense fibrous network of collagen IV with chambers that surrounded live nucleated cells and large amounts of necrotic cell debris. Tumors from the mice fed with the NM exhibited a well-defined border of fibronectin in the capsule and intense areas of staining internally whereas control group tumors showed less overall fibronectin with sporadic internal staining and little in the fibrous capsule. Although laminin appeared abundantly in control and NM-treated tumors, the NM group tumors exhibited a chamber-like network of laminin internally. Tumors from the control group exhibited internal areas of intense PAS staining, whereas tumors from the NM-treated group exhibited a more uniform diffuse pattern of PAS staining. In conclusion, NM supplementation of HeLa xenograft-bearing female nude mice demonstrated a potent inhibition of tumor growth and enhancement of ECM proteins, suggesting the therapeutic value of this specific nutrient complex in the treatment of cervical cancer.

Essential amino acid mixtures drive cancer cells to apoptosis through proteasome inhibition and autophagy activation

“…The relation between nutrition and cancer is an unresolved question with many possible answers since even cancer cells' peculiar energy production from glucose is still debated [29]. Nutrients in the diet may influence cancer development [3,6,16,18,28]. Supplementation with balanced formulations of EAAs exerted positive effects in the prevention of several human pathologies, in the improvement of the quality of life, in reducing oxidative damage and in increasing average life span in mice [3,6,13,14,16,17].…”

“…Nutrients in the diet may influence cancer development [3,6,16,18,28]. Supplementation with balanced formulations of EAAs exerted positive effects in the prevention of several human pathologies, in the improvement of the quality of life, in reducing oxidative damage and in increasing average life span in mice [3,6,13,14,16,17]. While AAs are indispensable for cells life, AA-induced cytotoxicity is documented in cancer cells, but few data are available on the molecular mechanisms involved [6,19,30].…”

“…Roomi et al . tested the effects of a nutrient mixture containing lysine, ascorbic acid, proline, green tea extract and other micronutrients on HeLa xenograft‐bearing female nude mice, demonstrating the inhibition of tumor growth and the enhancement of extracellular matrix proteins, suggesting its therapeutic value in the treatment of cervical cancer. Tumor growth inhibition and decrease of the values of several cancer markers, including Ki67, matrix metalloproteinase‐2 and ‐9, vascular endothelial growth factor, terminal deoxynucleotidyl transferase dUTP nick end labeling and B‐cell lymphoma 2, cyclooxygenase 2, inducible nitric oxide synthase and glutathione S ‐transferase π, were observed .…”

The role of antioxidant vitamins in gynecologic malignancies

“…Badania na myszach pozwoliły zaobserwować wpływ witaminy C na hamowanie rozwoju raka szyjki macicy. U chorych zwierząt odnotowano znacząco mniejsze wewnątrzkomórkowe stężenia witaminy C (45) . Zastosowanie cisplatyny (2-10 µM) wraz z witaminą C (1 µM) zwiększyło cytotoksyczność terapii (46) .…”

A comprehensive anticancer molecular study for genistein the promising anticancer drug

“…In contrast, it is fully treatable in the early stages. 4 Recently, an important natural inhibitor of cancer metastasis; genistein, has emerged, which is widely distributed in beans. Moreover, diet with genistein; the bioactive molecule ("nutraceutical"), has been linked to reduce the rate of cancer metastasis in a number of population-based studies.…”