Effect of pO2 on Antitumor Drug Cytotoxicity on MDR and Non-MDR Variants Selected from the LoVo Metastatic Colon Carcinoma Cell Line

• Published in: Anticancer research Vol. 28; no. 1A; pp. 55 - 68
• Main Authors: LELONG-REBEL, Isabelle, BRISSON, Christine, FABRE, Michel, BERGERAT, Jean-Pierre, REBEL, Gérard
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01-01-2008
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antioxidants - pharmacology; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biochemistry, Molecular Biology; Biological and medical sciences; Biomarkers, Tumor - metabolism; Cell Growth Processes - drug effects; Cell Line, Tumor; Cellular Biology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Life Sciences; Medical sciences; Mucin-2; Mucins - biosynthesis; Oxygen - administration & dosage; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Sucrase-Isomaltase Complex - metabolism; Tumors; Vinblastine - administration & dosage; Vinblastine - pharmacology; Antineoplastic agent; multidrug resistance; Genetic variability; antioxidants; cell lines; P Glycoprotein; Cytotoxicity; Metastasis; Colon cancer; Cancerology; Multiple resistance; Established cell line; Intestinal disease; Advanced stage; Drug; Treatment resistance; Genotype; Malignant tumor; Antioxidant; Colonic disease; Variant; P-glycoprotein; pO2; Digestive diseases; Colon carcinoma; Cancer
• ISSN: 0250-7005; 1791-7530

Two chemosensitive cell lines, LoVo-fusoid (LoVo-f) and LoVo-small cells (LoVo-sc) were derived from the original LoVo cell
line. These two variants and the multidrug-resistant (MDR) cell line LoVo-Dox were screened for various properties. In non-permeabilized
cells, only LoVo-sc showed mucin-2 staining whereas labelling was positive in all permeabilized cell lines. As shown by electron
microscopy screening and by relative resistance to trypsin detachment, only LoVo-sc cells showed strong mucus secretion. All
three cell lines displayed strong staining for P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and lung-resistance-related
protein (LRP) in different locations according to the drug resistance state. The three cell lines showed intracellular labelling
of LRP and MRP. The sensitive cells showed P-gp in a large perinuclear ring and in the cytoplasm, but little (LoVo-sc cells)
or no staining (LoVo-f cells) was shown at the plasma membrane level. For the Lovo-Dox cells, P-gp was located in the plasma
membrane, in cellular anchorages and in the cytoplasm as well. Cell resistance against antineoplastic agents often results
from mobilization of various factors, the modulation of which is linked to the culture conditions. As most of the protocols
utilize cells growing in (air+5-10% CO 2 ) atmosphere e.g. 20% O 2 , balance of the respective participants in the MDR multi-modal mechanism may not be representative of the in vivo situation
and may lead to erratic pharmacological response. Indeed, cells within solid tumours were exposed to low pO 2 , most of them being under hypoxic condition (0.1-5% O 2 ). In the absence of anticancer drugs, all LoVo cell lines grew notably faster at 20% O 2 than at 5% O 2 . Moreover, respective sensitivities of both non-MDR variants to doxorubicin were altered according the pO 2 . Whatever the pO 2 was, virtually none of the antioxidants tested affected the cytotoxic activity of doxorubicin for the three cell lines. By
contrast, trolox showed a strong inhibitory effect on doxorubicin activity. These results underline the importance of evaluating
the role of hypoxia on the cytotoxic effect of chemotherapeutic agents used either as single drugs or in combination therapy.