Adriamycin-induced inhibition of melanoma cell invasion is correlated with decreases in tumor cell motility and increases in focal contact formation

Abstract

Tumor cell adhesion to the extracellular matrix (ECM) is closely linked with tumor cell invasion and metastasis. In this study, we demonstrate that low levels of adriamycin, a widely used anticancer drug, can inhibit the invasion of highly metastatic K1735-M2 mouse melanoma cells in vitro through a reconstituted basement membrane extract. Adriamycin-induced inhibition of melanoma cell invasion occurred at levels of the drug (i.e. 1 ng/ml) that did not inhibit tumor cell growth, suggesting that the observed inhibition in tumor cell invasion was not due to the well-documented ability of adriamycin to interfere with DNA and/or RNA synthesis. Rather, these studies indicated that adriamycin-induced inhibition of melanoma cell invasion was accompanied by a corresponding decrease in the ability of adriamycin-treated tumor cells to migrate in response to several isolated ECM components including fibronectin, laminin and basement membrane (type IV) collagen. The decreased migration of adriamycin-treated tumor cells was not accompanied by a decrease in the adhesion or spreading of the adriamycin-treated cells on substrata coated with these ECM components. Instead, adriamycin-treated cells actually exhibited a slightly increased propensity (compared to untreated control cells) to adhere on fibronectin-, laminin-, and type IV collagen-coated substrata. Additionally, adriamycin treatment caused a dramatic increase in focal contact formation by these melanoma cells, as assessed by fluorescent microscopy of actin and vinculin. In addition to providing a useful model for which to study the molecular and cellular basis for focal contact formation, these results further emphasize the results of several other investigators that have suggested an important role for focal contacts in modulating tumor cell motility, invasion and metastasis.

Influence of stress on extracellular matrix and integrin biology

“…However, some observations suggest that, these agents might influence focal adhesion zone formation (Repesh et al, 1993) as well as phosphorylation of FAK (Repesh et al, 1993;van Nimwegen et al, 2006), p130Cas and paxillin (Beinke et al, 2003). This could explain the anti-metastasis properties of some anti-cancer drugs such as anthracyclines (Repesh et al, 1993). Conversely, as it is suggested by the MDR cell profile, chronic exposure to drugs may result in reduced integrin expression and function with significant consequences on cell adhesion and migration (Duensing et al, 1996;Liang et al, 2001;Kozlova et al, 2004).…”

“…However, some observations suggest that, these agents might influence focal adhesion zone formation (Repesh et al, 1993) as well as phosphorylation of FAK (Repesh et al, 1993;van Nimwegen et al, 2006), p130Cas and paxillin (Beinke et al, 2003). This could explain the anti-metastasis properties of some anti-cancer drugs such as anthracyclines (Repesh et al, 1993).…”

p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

“…However, recent study has shown that Adriamycin at non-cytotoxic concentrations reduced the invasive behavior of human melanoma cell by suppressing collagenase-1 expression [36]. In addition, Adriamycin at low concentrations lower than those used to suppress cell growth, can inhibit invasion and migration of mouse melanoma cell by modulating cell adhesion [37]. All these findings suggested that Adriamycin-induced inhibition of cell invasion and migration was not solely due to the ability of Adriamycin to cause DNA damage, which triggers p53 protein elevations [38].…”

A new superinvasive in vitro phenotype induced by selection of human breast carcinoma cells with the chemotherapeutic drugs paclitaxel and doxorubicin

“…Sgadari et al (2000) found that paclitaxel promoted regression of Kaposi's sarcoma (KS) lesions in vivo and that it blocked the growth, migration, and invasion of KS cells in vitro. Doxorubicin appears to have an inhibitory effect on invasion (Repesh et al, 1993;Hikawa et al, 2000).Previous studies in this laboratory showed that selection of RPMI 2650, a noninvasive cell line, with the chemotherapeutic agents paclitaxel and melphalan, resulted in multiple drugresistant phenotypes and in the case of melphalan but not paclitaxel, a highly invasive phenotype (Liang et al, 2001). To further investigate the effects of chemotherapeutic drug selection, in particular doxorubicin and paclitaxel, and the effect of these drugs on adhesive, locomotive and invasive phenotypes, paclitaxeland doxorubicin-selected variants of the human breast cell line MDA-MB-435S-F were established.…”

“…Sgadari et al (2000) found that paclitaxel promoted regression of Kaposi's sarcoma (KS) lesions in vivo and that it blocked the growth, migration, and invasion of KS cells in vitro. Doxorubicin appears to have an inhibitory effect on invasion (Repesh et al, 1993;Hikawa et al, 2000).…”