An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer

Abstract

BackgroundPancreatic cancer is a deadly disease with a very low 5-year patient survival rate of 6–8%. The major challenges of eliminating pancreatic cancer are treatment resistance and stromal barriers to optimal drug access within the tumor. Therefore, effective molecular targeting drugs with high intra-tumor access and retention are urgently needed for managing this devastating disease in the clinic.MethodsThis study has used the following in vitro and in vivo techniques for the investigation of exceptional anticancer drug FL118’s efficacy in treatment of resistant pancreatic cancer: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs.ResultsOur studies found that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, using in vivo-imaging, we found that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. In PDX model, we demonstrated that FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118. These FL118 efficacy results are consistent with our molecular-targeting data showing that FL118 inhibited the expression of multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and ERCC6, a critical regulator of DNA repair, in treatment-resistant pancreatic stem-like cancer cells. Furthermore, FL118 toxicity studies in BALB/cj mice and beagle dogs indicated that FL118 exhibits favorable hematopoietic and biochemical toxicities.ConclusionTogether, our studies suggest that FL118 is a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs.

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

“…Consistently, FL118 appears to use multiple mechanisms to induce pancreatic cancer killing as well [80,98]. Furthermore, toxicity studies with FL118 at low, middle and high doses in beagle dogs indicated that at only the high dose, some of the 39 hematopoietic and biochemical parameters tested slightly changed without other FL118-related clinical observations including dog behavior, food consumption and body weights [80].…”

“…DNA microarray studies showed that FL118 does not inhibit the expression of cIAP1, Bcl-2, Bcl-XL, Bcl-2, Bcl2A1, Bcl-w, Bcl-B, Bcl2L12, Bcl2L13, Bcl-G and Bcl2L15 (unpublished data), indicating additional selectivity of FL118 in its molecular targets. Furthermore, FL118 also inhibits MdmX/Mdm4 [79], a critical oncogenic protein involved in p53 pathway, and ERCC6 [80], a critical regulator in DNA repair. Importantly, while FL118 downregulation of MdmX induced senescence in cancer cells with wild type p53, FL118 exhibits even higher efficacy to inhibit cell growth and induce apoptosis in cancer cells without functional p53 (mutated or null) [79].…”

“…Along with the versatile and unique features of FL118 summarized above, FL118 has shown striking antitumor activity in human tumor animal models [63,68,78,80,95,96]. FL118 exhibited significantly superior antitumor activity when compared with FDA-approved anticancer drugs commonly used in clinical practice (irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin) [63].…”

“…Recent studies indicate that FL118 targets cancer stem cells (CSCs) by inhibiting a number of CSC markers and drug resistant proteins in lung cancer [97]. FL118 preferentially targets and kills cisplatin-resistant pancreatic cancer cells, and inhibits spheroid formation of pancreatic cancer stem cells [80]. Studies from the In vivo animal models of human pancreatic cancer patient-derived xenograft (PDX) tumors indicated that alone, FL118 effectively eliminated PDX tumors, while FL118 in combination with gemcitabine (a first line pancreatic cancer drug) eliminated PDX tumors that showed resistance/ non-sensitivity to FL118 and gemcitabine treatment [80].…”

Preclinical evidence for an effective therapeutic activity of FL118, a novel survivin inhibitor, in patients with relapsed/refractory multiple myeloma

“…5 In addition, FL118 was shown to selectively and independently inhibit additional anti-apoptotic genes including Mcl-1, XIAP and cIAP2. In preclinical settings, FL118 showed a favorable toxicity profile in experimental animals, 6 and an effective antitumor activity against human colon and head-and-neck tumors in a topoisomerase I-and P53 status-independent manner. 5,7 The latter is of importance for MM, since mutations or the loss of P53 encoding gene, as through the deletion of chromosome 17p, are characteristics of high-risk MM with poor prognosis.…”