A lipophilic vasoactive intestinal peptide analog enhances the antiproliferative effect of chemotherapeutic agents on cancer cell lines

Abstract

BACKGROUND Vasoactive intestinal peptide (VIP) is one of several small neuropeptides that affect cancer growth. A lipophilic VIP analog, stearyl‐Nle17‐neuroten‐ sin6‐11VIP7‐28 (SNH) that inhibited lung carcinoma growth has been described previously. The experiments performed were clonogenic assays in vitro and tumor xenografts in nude mice in vivo. These studies were now extended to colon carcinoma and to combination therapy with chemotherapeutic agents. METHODS Assays were performed with cell lines, and tumor proliferation was assessed using the (3‐[4,5‐dimethylthiazol‐2‐yl‐5]‐[3‐carboxymethoxyphenyl]‐2‐[4‐sulfophenyl]‐2H tetrazolium) (MTS) colorimetric assay for mitochondrial function of living cells. RESULTS The lipophilic analog (SNH) enhanced the antiproliferative activity of diverse chemotherapeutic agents: doxorubicine (antibiotic); vinorelbine (vinca alkaloid, antimicrotubule formation); paclitaxel (antimicrotubule agent); gemcitabine (antimetabolite); irinotecan (topoisomerase I inhibitor); and cisplatin (platinum compound acting as an alkylating agent). In all cases, the antiproliferative effect of SNH and the chemotheraputic agent was at least additive and for some combinations and concentrations even synergistic. For example, 2 μM of the antagonist that produced a 15–20% growth inhibition in the nonsmall cell lung carcinoma cell line reduced the IC50 by 2–4‐fold for most of the chemotherapeutic agents tested. Higher analog concentrations were even more efficacious. Similar results were obtained with colon carcinoma cell lines. CONCLUSIONS Chemotherapeutic treatment of advanced solid tumors, such as nonsmall cell lung carcinoma, colon carcinoma, or prostate carcinoma, achieves a response rate of between 10% and 30% with significant toxicity. Combination therapy with the lipophilic VIP analog SNH and the preferred chemotherapeutic agent may greatly enhance the response rate, and by permitting a dose reduction, should significantly reduce side effects. Cancer 2001;92:2172–80. © 2001 American Cancer Society.

Immunocytochemical Identification of VPAC1, VPAC2, and PAC1 Receptors in Normal and Neoplastic Human Tissues with Subtype-Specific Antibodies

“…VPAC 1 in myenteric nerve fibers is likely to function as autoreceptor, regulating the release of VIP and PACAP. VPAC 2 in neuroendocrine cells may also function as autoreceptor, which may explain the high levels of internalized receptors detected in these (2,3,(27)(28)(29)(30)(31)(32)(33). Whereas growth-promoting activities have been reported for VIP, growth-inhibiting properties have been found for VIP antagonists in various tumor models (2,3,(27)(28)(29)(30)(31)(32)(33).…”

“…Second, VIP/PACAP receptor-positive intestinal and endocrine tumors can be visualized by in vivo VIP receptor scintigraphy (1,4,6,(23)(24)(25)(26). Third, application of VIP and PACAP analogs modulates tumor growth in animal models (2,3,(27)(28)(29)(30)(31)(32)(33).…”

Vasoactive intestinal peptide–camptothecin conjugates inhibit the proliferation of breast cancer cells

“…Basic amino acids of VIP such as Arg 14 , Lys 15 and Lys 21 may interact electrostatically with acidic amino acids such as Glu 36 on the VPAC 1 -R [36]. Substitution of Ala for VIP amino acids at positions 1, 6, 12, 14 or 23 reduced binding affinity to VPAC 1 -R by over 2-orders of magnitude [19,36].…”

“…VIP receptor antagonists such as VIPhybrid or (N-Stearyl 1 , Nle 17 )VIP not only inhibit the proliferation of lung and breast cancer cells [17,34], but they potentiate the cytotoxicity of chemotherapeutic agents [14,31]. The overexpression of peptide receptors by the tumor can be used for receptor-targeted delivery of peptide receptor cytotoxic agents [35].…”

Gene expression of vasoactive intestinal peptide receptors in human lung cancer

“…This attenuation of tumor proliferation was proven to be receptormediated as the VIPhybrid inhibited the specific 125 I-labeled VIP binding to NSCLC cell lines (14). It was also demonstrated that the VIPhybrid potentiates the cytotoxicity of chemotherapeutic agents in cancer cell lines (15). Vasoactive intestinal peptide/growth hormone-releasing hormone (VIP/ GHRH) antagonists, such as JV-1-52 and JV-1-53 constructed by our group, were also able to inhibit the growth of androgenindependent prostate cancers by abrogating the autocrine/ paracrine mitogenic stimuli of VIP (16).…”