Pramlintide, an antidiabetic, is antineoplastic in colorectal cancer and synergizes with conventional chemotherapy

Abstract

BackgroundApproximately 90% of patients with metastatic colorectal cancer fail therapy mainly due to resistance. Taking advantage of currently approved agents for treatment of disease conditions other than cancer for the identification of new adjuvant anticancer therapies is highly encouraged. Pramlintide is a parenteral antidiabetic agent that is currently approved for treatment of types 1 and 2 diabetes mellitus.ObjectivesTo address the antineoplastic potential of pramlintide in colorectal cancer and to evaluate the ability of pramlintide to enhance the cytotoxicity of 5-fluorouracil, oxaliplatin, and irinotecan against colorectal cancer cell lines expressing wild-type and mutant p53.Materials and methodsThe antiproliferative effect of pramlintide alone or in combination with 5-fluorouracil, oxaliplatin, or irinotecan in HCT-116 and HT-29 colorectal cancer cell lines was investigated using MTT cell proliferation assay. IC50 values were calculated using Compusyn software 1.0. Synergy values (R) were calculated using the ratio of IC50 of each primary drug alone divided by combination IC50s. For each two pairs of experiments, Student’s t-test was used for analysis. For combination studies, one-way analysis of variance and Tukey post hoc testing was performed using R 3.3.2 software. A p-value of <0.05 was considered significant.ResultsPramlintide inhibited the growth of HCT-116 and HT-29 in a dose-dependent manner, with higher efficacy against the latter (IC50s; 48.67 and 9.10 μg/mL, respectively; p-value =0.013). Moreover, the addition of 5, 10, and 20 μg/mL of pramlintide to HCT-116 and HT-29 with 5-fluorouracil, oxaliplatin, or irinotecan induced the antiproliferative effect synergistically (R>1.6, p-value <0.05).ConclusionPramlintide enhances the cytotoxicity of conventional chemotherapy against colorectal cancer cell lines harboring wild-type or mutant p53. Thus, pramlintide is a promising potential adjuvant chemotherapy in colorectal cancer.

Impaired Glucose Metabolism, Anti-Diabetes Medications, and Risk of Thyroid Cancer

“…Pramlintide is a synthetic analog of amylin that is co-secreted with insulin by pancreatic β-cells. Pramlintide had anticancer effects in thymic lymphomas and colorectal cell lines via p53-dependent effects [138,139]. Pramlintide also showed synergistic benefits with chemotherapeutic agents [138].…”

“…Pramlintide had anticancer effects in thymic lymphomas and colorectal cell lines via p53-dependent effects [138,139]. Pramlintide also showed synergistic benefits with chemotherapeutic agents [138]. Currently, there is no known association of pramlintide with thyroid cancer.…”

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

“…Pramlintide, a synthetic analog of AMY, stimulated tumor regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers [ 279 ]. Pramlintide also exerted an antiproliferative action against colorectal cancer cells, and its coadministration with classic chemotherapeutics increased cytotoxicity [ 366 ].…”

“…AMY induces apoptosis in thymic lymphoma via the RAMP3/CT receptor [ 279 ]. Moreover, pramlintide, a synthetic analog of AMY, exerted an antiproliferative action against tumor cells, and its coadministration with chemotherapeutics increased cytotoxicity [ 366 ]. This knowledge is important for developing new antitumor strategies.…”

Islet amyloid polypeptide does not suppress pancreatic cancer

“…Similar to other amyloidogenic peptides, monomers and elongated fibrils show negligible toxicity, while intermediate oligomeric aggregates are thought to confer the majority of cellular toxicity [ [16] , [17] , [18] , [19] ]. Monomeric IAPP was, however, reported to have potent anti-tumour effects in p53-deficient cancers through inhibition of glycolysis and proliferation, and stimulation of apoptosis [ [20] , [21] , [22] ]. The non-aggregating FDA-approved IAPP analog, pramlintide, was reported to rapidly induce regression of p53-deficient thymic lymphomas in mice over a 3-week period with only twice-weekly injections [ 20 ].…”