LH-RH receptors in human colorectal cancers: Unexpected molecular targets for experimental therapy

Abstract

Abstract. Since the efficacy of chemotherapy can be enhanced by targeting to specific receptors on tumors, we investigated the expression of LH-RH receptors in 5 human colon cancer lines and the effects of cytotoxic LH-RH analogs on these tumors. Nude mice bearing HT-29, HCT-116, HCT-15, LoVo and Colo-320DM cancers were treated with cytotoxic LH-RH analogs AN-152 and AN-207 or their respective cytotoxic radicals doxorubicin (DOX) and 2-pyrrolino-DOX (AN-201). The reduction in tumor growth was evaluated, and cell proliferation characteristics as well as apoptosis were analyzed by histological methods. LH-RH receptors on the tumors were investigated by radioligand binding assays and their mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR). All 5 colorectal cancer lines expressed high affinity binding sites for LH-RH, and mRNA for the LH-RH receptors. Both cytotoxic LH-RH analogs AN-152 and AN-207 powerfully inhibited growth of all colon cancers. AN-207 had the strongest effect on HT-29 and HCT-116 tumors, and AN-152 was the most effective on Colo-320DM cancers. Cytotoxic radicals AN-201 and DOX were less effective on these 3 tumors, but had effects similar to AN-152 and AN-207 on HCT-15 and LoVo carcinomas. The four cytotoxic compounds also differently affected apoptosis and proliferation rate of the various tumor lines. Our findings suggest that cytotoxic LH-RH analogs should be considered for the therapy of patients with advanced colorectal carcinoma.

Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review)

“…These include liver (63), larynx (64), pancreas (65), colon (66), lymphoma (67), kidney (68,69), skin (70,71), leukemia (49) and brain (72). The function of GnRH and GnRHR in these tumors has been associated with inhibition of proliferation in a time-and dose-related manner in respond to various molecular form of GnRH (63)(64)(65)(66)(67)(68)(69)(70)(71)(72). The response to GnRH in pancreatic tumors has been shown to be specific, it was demonstrated by the absences of binding sites for GnRH in membranes from nontumoral human pancreas tissues (65,73).…”

Triple-negative breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH) and respond to LHRH antagonist Cetrorelix with growth inhibition

“…Specific receptors for LHRH were detected on human breast, prostatic, ovarian, endometrial and pancreatic cancers (8)(9)(10)(11)(12)(13)(14)(15)(16). In an unselected series of human breast cancer samples (containing steroid receptor positive and negative as well as HER2-positive and -negative samples) our group detected high-affinity binding sites for LHRH in >50% of the cases.…”

“…Specific receptors for luteinizing hormone-releasing hormone (LHRH) have been so far detected on a variety of human cancer cells, such as breast, prostatic, ovarian, endometrial, colorectal and pancreatic cancers as well as melanomas and non-Hodgkin's lymphoma (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The production of an LHRH-like peptide and/or the expression of mRNA for LHRH was also demonstrated in various human cancer cell lines (8,14,18).…”

“…Targeted cytotoxic LHRH analogs also inhibit the growth of human mammary, prostatic, ovarian, endometrial, colorectal cancers as well as melanomas, non-Hodgkin's lymphomas and renal carcinomas xenografted into nude mice (12,15,18,22,26).…”

LHRH receptor expression in sarcomas of bone and soft tissue

“…To date, their expression on sarcomas, with the exception of endometrial sarcomas, has not been studied. It has been demonstrated that both LHRH agonists and antagonists can inhibit the growth of these tumor cells [17][18][19]. A further major therapeutic implication is that the cells expressing these receptors can be targeted even more effectively by conjugating cytotoxic moieties to the LHRH agonists, a 3rd type of analog.…”