Vitamin D derivatives potentiate the anticancer and anti-angiogenic activity of tyrosine kinase inhibitors in combination with cytostatic drugs in an A549 non-small cell lung cancer model

Maj,Ewa; Filip-Psurska,Beata; Milczarek,Magdalena; Psurski,Mateusz; Kutner,Andrzej; Wietrzyk,Joanna

doi:10.3892/ijo.2017.4228

Vitamin D derivatives potentiate the anticancer and anti-angiogenic activity of tyrosine kinase inhibitors in combination with cytostatic drugs in an A549 non-small cell lung cancer model

Authors:
- Ewa Maj
- Beata Filip-Psurska
- Magdalena Milczarek
- Mateusz Psurski
- Andrzej Kutner
- Joanna Wietrzyk
View Affiliations

Affiliations: Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland, Pharmaceutical Research Institute, 01-793 Warsaw, Poland
Published online on: December 15, 2017 https://doi.org/10.3892/ijo.2017.4228
Pages: 337-366
Copyright: © Maj et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Numerous in vitro and in vivo studies have demonstrated that calcitriol [1,25(OH)2D3] and different vitamin D analogs possess antineoplastic activity, regulating proliferation, differentiation and apoptosis, as well as angiogenesis. Vitamin D compounds have been shown to exert synergistic effects when used in combination with different agents used in anticancer therapies in different cancer models. The aim of this study was to evaluate the mechanisms of the cooperation of the vitamin D compounds [1,24(OH)2D3 (PRI‑2191) and 1,25(OH)2D3] with tyrosine kinase inhibitors (imatinib and sunitinib) together with cytostatics (cisplatin and docetaxel) in an A549 non-small cell lung cancer model. The cytotoxic effects of the test compounds used in different combinations were evaluated on A549 lung cancer cells, as well as on human lung microvascular endothelial cells (HLMECs). The effects of such combinations on the cell cycle and cell death were also determined. In addition, changes in the expression of proteins involved in cell cycle regulation, angiogenesis and the action of vitamin D were analyzed. Moreover, the effects of 1,24(OH)2D3 on the anticancer activity of sunitinib and sunitinib in combination with docetaxel were examined in an A549 lung cancer model in vivo. Experiments aiming at evaluating the cytotoxicity of the combinations of the test agents revealed that imatinib and sunitinib together with cisplatin or docetaxel exerted potent anti-proliferative effects in vitro on A549 lung cancer cells and in HLMECs; however, 1,24(OH)2D3 and 1,25(OH)2D3 enhanced the cytotoxic effects only in the endothelial cells. Among the test agents, sunitinib and cisplatin decreased the secretion of vascular endothelial growth factor (VEGF)‑A from the A549 lung cancer cells. The decrease in the VEGF‑A level following incubation with cisplatin correlated with a higher p53 protein expression, while no such correlation was observed following treatment of the A549 cells with sunitinib. Sunitinib together with docetaxel and 1,24(OH)2D3 exhibited a more potent anticancer activity in the A549 lung cancer model compared to double combinations and to treatment with the compounds alone. The observed anticancer activity may be the result of the influence of the test agents on the process of tumor angiogenesis, for example, through the downregulation of VEGF‑A expression in tumor and also on the induction of cell death inside the tumor.

View Figures

View References

1	Adler I: Primary Malignant Growths of the Lungs and Bronchi; A Pathological and Clinical Study. Longmans; Green, New York, NY: 1912
2	Debakey M: Carcinoma of the lung and tobacco smoking: A historical perspective. Ochsner J. 1:106–108. 1999.PubMed/NCBI
3	Proctor RN: The history of the discovery of the cigarette-lung cancer link: Evidentiary traditions, corporate denial, global toll. Tob Control. 21:87–91. 2012. View Article : Google Scholar : PubMed/NCBI
4	Dubey AK, Gupta U and Jain S: Epidemiology of lung cancer and approaches for its prediction: A systematic review and analysis. Chin J Cancer. 35:712016. View Article : Google Scholar : PubMed/NCBI
5	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
6	Gadgeel SM, Ramalingam SS and Kalemkerian GP: Treatment of lung cancer. Radiol Clin North Am. 50:961–974. 2012. View Article : Google Scholar : PubMed/NCBI
7	Feldman D, Krishnan AV, Swami S, Giovannucci E and Feldman BJ: The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 14:342–357. 2014. View Article : Google Scholar : PubMed/NCBI
8	Slominski AT, Brożyna AA, Zmijewski MA, Jóźwicki W, Jetten AM, Mason RS, Tuckey RC and Elmets CA: Vitamin D signaling and melanoma: Role of vitamin D and its receptors in melanoma progression and management. Lab Invest. 97:706–724. 2017. View Article : Google Scholar : PubMed/NCBI
9	Higashimoto Y, Ohata M, Nishio K, Iwamoto Y, Fujimoto H, Uetani K, Suruda T, Nakamura Y, Funasako M and Saijo N: 1 alpha, 25-dihydroxyvitamin D3 and all-trans-retinoic acid inhibit the growth of a lung cancer cell line. Anticancer Res. 16(5A): 2653–2659. 1996.PubMed/NCBI
10	Güzey M, Sattler C and DeLuca HF: Combinational effects of vitamin D3 and retinoic acid (all trans and 9 cis) on proliferation, differentiation, and programmed cell death in two small cell lung carcinoma cell lines. Biochem Biophys Res Commun. 249:735–744. 1998. View Article : Google Scholar : PubMed/NCBI
11	Young MRI, Ihm J, Lozano Y, Wright MA and Prechel MM: Treating tumor-bearing mice with vitamin D3 diminishes tumor-induced myelopoiesis and associated immunosuppression, and reduces tumor metastasis and recurrence. Cancer Immunol Immunother. 41:37–45. 1995.PubMed/NCBI
12	Young MRI, Lozano Y, Ihm J, Wright MA and Prechel MM: Vitamin D3 treatment of tumor bearers can stimulate immune competence and reduce tumor growth when treatment coincides with a heightened presence of natural suppressor cells. Cancer Lett. 104:153–161. 1996. View Article : Google Scholar : PubMed/NCBI
13	Norton R and O'Connell MA: Vitamin D: Potential in the prevention and treatment of lung cancer. Anticancer Res. 32:211–221. 2012.PubMed/NCBI
14	Mernitz H, Smith DE, Wood RJ, Russell RM and Wang XD: Inhibition of lung carcinogenesis by 1alpha,25-dihydroxyvitamin D3 and 9-cis retinoic acid in the A/J mouse model: Evidence of retinoid mitigation of vitamin D toxicity. Int J Cancer. 120:1402–1409. 2007. View Article : Google Scholar : PubMed/NCBI
15	Yudoh K, Matsuno H and Kimura T: 1alpha,25-dihydroxyvitamin D3 inhibits in vitro invasiveness through the extracellular matrix and in vivo pulmonary metastasis of B16 mouse melanoma. J Lab Clin Med. 133:120–128. 1999. View Article : Google Scholar : PubMed/NCBI
16	Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y and Mabjeesh NJ: 1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther. 6:1433–1439. 2007. View Article : Google Scholar : PubMed/NCBI
17	Chung I, Han G, Seshadri M, Gillard BM, Yu WD, Foster BA, Trump DL and Johnson CS: Role of vitamin D receptor in the anti-proliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo. Cancer Res. 69:967–975. 2009. View Article : Google Scholar : PubMed/NCBI
18	Bao BY, Yao J and Lee YF: 1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis. 27:1883–1893. 2006. View Article : Google Scholar : PubMed/NCBI
19	Crino L and Metro G: Therapeutic options targeting angiogenesis in nonsmall cell lung cancer. Eur Respir Rev. 23:79–91. 2014. View Article : Google Scholar : PubMed/NCBI
20	McMahon G: VEGF receptor signaling in tumor angiogenesis. Oncologist. 5(Suppl 1): 3–10. 2000. View Article : Google Scholar : PubMed/NCBI
21	Sandler A, Yi J, Dahlberg S, Kolb MM, Wang L, Hambleton J, Schiller J and Johnson DH: Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer. J Thorac Oncol. 5:1416–1423. 2010. View Article : Google Scholar : PubMed/NCBI
22	Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R and Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 355:2542–2550. 2006. View Article : Google Scholar : PubMed/NCBI
23	Aggarwal C, Somaiah N and Simon G: Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed? Cancer Biol Ther. 13:247–263. 2012. View Article : Google Scholar : PubMed/NCBI
24	Calero R, Morchon E, Johnsen JI and Serrano R: Sunitinib suppress neuroblastoma growth through degradation of MYCN and inhibition of angiogenesis. PLoS One. 9:e956282014. View Article : Google Scholar : PubMed/NCBI
25	Teodoro JG, Evans SK and Green MR: Inhibition of tumor angiogenesis by 53: A new role forthe guardian of the genome. J Mol Med (Berl). 85:1175–1186. 2007. View Article : Google Scholar
26	Wietrzyk J, Nevozhay D, Filip B, Milczarek M and Kutner A: The antitumor effect of lowered doses of cytostatics combined with new analogs of vitamin D in mice. Anticancer Res. 27(5A): 3387–3398. 2007.PubMed/NCBI
27	Wietrzyk J, Nevozhay D, Milczarek M, Filip B and Kutner A: Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model. Cancer Chemother Pharmacol. 62:787–797. 2008. View Article : Google Scholar : PubMed/NCBI
28	Milczarek M, Rosinska S, Psurski M, Maciejewska M, Kutner A and Wietrzyk J: Combined colonic cancer treatment with vitamin D analogs and irinotecan or oxaliplatin. Anticancer Res. 33:433–444. 2013.PubMed/NCBI
29	Milczarek M, Psurski M, Kutner A and Wietrzyk J: Vitamin D analogs enhance the anticancer activity of 5-fluorouracil in an in vivo mouse colon cancer model. BMC Cancer. 13:2942013. View Article : Google Scholar : PubMed/NCBI
30	Milczarek M, Filip-Psurska B, Swiętnicki W, Kutner A and Wietrzyk J: Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment. Oncol Rep. 32:491–504. 2014. View Article : Google Scholar : PubMed/NCBI
31	Maj E, Filip-Psurska B, Świtalska M, Kutner A and Wietrzyk J: Vitamin D analogs potentiate the antitumor effect of imatinib mesylate in a human A549 lung tumor model. Int J Mol Sci. 16:27191–27207. 2015. View Article : Google Scholar : PubMed/NCBI
32	Trynda J, Turlej E, Milczarek M, Pietraszek A, Chodyński M, Kutner A and Wietrzyk J: Antiproliferative activity and in vivo toxicity of double-point modified analogs of 1,25-dihydroxyergocalciferol. Int J Mol Sci. 16:24873–24894. 2015. View Article : Google Scholar : PubMed/NCBI
33	Kieda C, Paprocka M, Krawczenko A, Załecki P, Dupuis P, Monsigny M, Radzikowski C and Duś D: New human microvascular endothelial cell lines with specific adhesion molecules phenotypes. Endothelium. 9:247–261. 2002. View Article : Google Scholar
34	Nevozhay D: Cheburator software for automatically calculating drug inhibitory concentrations from in vitro screening assays. PLoS One. 9:e1061862014. View Article : Google Scholar : PubMed/NCBI
35	McDaid HM and Johnston PG: Synergistic interaction between paclitaxel and 8-chloro-adenosine 3′,5′-monophosphate in human ovarian carcinoma cell lines. Clin Cancer Res. 5:215–220. 1999.PubMed/NCBI
36	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
37	Chou TC and Talalay P: Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem. 115:207–216. 1981. View Article : Google Scholar : PubMed/NCBI
38	Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
39	Ekici OD, Li ZZ, Campbell AJ, James KE, Asgian JL, Mikolajczyk J, Salvesen GS, Ganesan R, Jelakovic S, Grütter MG, et al: Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10. J Med Chem. 49:5728–5749. 2006. View Article : Google Scholar : PubMed/NCBI
40	Ramnath N, Kim S and Christensen PJ: Vitamin D and lung cancer. Expert Rev Respir Med. 5:305–309. 2011. View Article : Google Scholar : PubMed/NCBI
41	Switalska M, Nasulewicz-Goldeman A, Opolska A, Maciejewska M, Kutner A and Wietrzyk J: The in-vitro antiproliferative effect of PRI-2191 and imatinib applied in combined treatment with cisplatin, idarubicin, or docetaxel on human leukemia cells. Anticancer Drugs. 23:70–80. 2012. View Article : Google Scholar
42	Pan F, Tian J, Zhang X, Zhang Y and Pan Y: Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. J Cancer Res Clin Oncol. 137:1397–1408. 2011. View Article : Google Scholar : PubMed/NCBI
43	Zhuravel E, Efanova O, Shestakova T, Glushko N, Mezhuev O, Soldatkina M and Pogrebnoy P: Administration of vitamin D3 improves antimetastatic efficacy of cancer vaccine therapy of Lewis lung carcinoma. Exp Oncol. 32:33–39. 2010.PubMed/NCBI
44	Socinski MA, Novello S, Brahmer JR, Rosell R, Sanchez JM, Belani CP, Govindan R, Atkins JN, Gillenwater HH, Pallares C, et al: Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol. 26:650–656. 2008. View Article : Google Scholar : PubMed/NCBI
45	Kerbel RS, Viloria-Petit A, Klement G and Rak J: 'Accidental' anti-angiogenic drugs. Anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer. 36:1248–1257. 2000. View Article : Google Scholar : PubMed/NCBI
46	Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P and Kerbel RS: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 105:R15–R24. 2000. View Article : Google Scholar : PubMed/NCBI
47	Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, Bohlen P, Hicklin DJ, Bergers G and Kerbel RS: Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res. 62:2731–2735. 2002.PubMed/NCBI
48	Kollmannsberger C, Soulieres D, Wong R, Scalera A, Gaspo R and Bjarnason G: Sunitinib therapy for metastatic renal cell carcinoma: Recommendations for management of side effects. Can Urol Assoc J. 1(Suppl): S41–S54. 2007.
49	Di Lorenzo G, Porta C, Bellmunt J, Sternberg C, Kirkali Z, Staehler M, Joniau S, Montorsi F and Buonerba C: Toxicities of targeted therapy and their management in kidney cancer. Eur Urol. 59:526–540. 2011. View Article : Google Scholar : PubMed/NCBI
50	Wietrzyk J, Pełczyńska M, Madej J, Dzimira S, Kuśnierczyk H, Kutner A, Szelejewski W and Opolski A: Toxicity and antineoplastic effect of (24R)-1,24-dihydroxyvitamin D3 (PRI-2191). Steroids. 69:629–635. 2004. View Article : Google Scholar : PubMed/NCBI
51	Díaz GD, Paraskeva C, Thomas MG, Binderup L and Hague A: Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: Possible implications for prevention and therapy. Cancer Res. 60:2304–2312. 2000.PubMed/NCBI
52	Pálmer HG, González-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M, et al: Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 154:369–387. 2001. View Article : Google Scholar : PubMed/NCBI
53	Teng CLJ, Yu CTR, Hwang WL, Tsai JR, Liu HC, Hwang GY and Hsu SL: Effector mechanisms of sunitinib-induced G1 cell cycle arrest, differentiation, and apoptosis in human acute myeloid leukaemia HL60 and KG-1 cells. Ann Hematol. 92:301–313. 2013. View Article : Google Scholar
54	Nishikawa M, Miyake H and Fujisawa M: Enhanced sensitivity to sunitinib by inhibition of Akt1 expression in human castration-resistant prostate cancer C3 cells both in vitro and in vivo. Urology. 85:1215.e1–1215.e7. 2015. View Article : Google Scholar
55	Uzu M, Sato H, Yamada R, Kashiba T, Shibata Y, Yamaura K and Ueno K: Effect of enhanced expression of connexin 43 on sunitinib-induced cytotoxicity in mesothelioma cells. J Pharmacol Sci. 128:17–26. 2015. View Article : Google Scholar : PubMed/NCBI
56	Stepień A, Izdebska M and Grzanka A: The types of cell death. Postepy Hig Med Dosw (Online). 61:420–428. 2007.In Polish.
57	Korwek Z and Alster O: The role of the DNA damage response in apoptosis and cell senescence. Postepy Biochem. 60:248–262. 2014.In Polish.
58	Koren R, Wacksberg S, Weitsman GE and Ravid A: Calcitriol sensitizes colon cancer cells to H₂O₂-induced cytotoxicity while inhibiting caspase activation. J Steroid Biochem Mol Biol. 101:151–160. 2006. View Article : Google Scholar : PubMed/NCBI
59	Diker-Cohen T, Koren R, Liberman UA and Ravid A: Vitamin D protects keratinocytes from apoptosis induced by osmotic shock, oxidative stress, and tumor necrosis factor. Ann N Y Acad Sci. 1010:350–353. 2003. View Article : Google Scholar
60	Lavallard VJ, Pradelli LA, Paul A, Bénéteau M, Jacquel A, Auberger P and Ricci JE: Modulation of caspase-independent cell death leads to resensitization of imatinib mesylate-resistant cells. Cancer Res. 69:3013–3020. 2009. View Article : Google Scholar : PubMed/NCBI
61	Costa PM, Cardoso AL, Nóbrega C, Pereira de Almeida LF, Bruce JN, Canoll P and Pedroso de Lima MC: MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma. Hum Mol Genet. 22:904–918. 2013. View Article : Google Scholar :
62	Liu ZL, Wang H, Liu J and Wang ZX: MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem. 372:35–45. 2013. View Article : Google Scholar
63	Xu L, Huang Y, Chen D, He J, Zhu W, Zhang Y and Liu X: Downregulation of miR-21 increases cisplatin sensitivity of non-small-cell lung cancer. Cancer Genet. 207:214–220. 2014. View Article : Google Scholar : PubMed/NCBI
64	Zhang YX, Yue Z, Wang PY, Li YJ, Xin JX, Pang M, Zheng QY and Xie SY: Cisplatin upregulates MSH2 expression by reducing miR-21 to inhibit A549 cell growth. Biomed Pharmacother. 67:97–102. 2013. View Article : Google Scholar : PubMed/NCBI
65	Vakifahmetoglu H, Olsson M and Zhivotovsky B: Death through a tragedy: Mitotic catastrophe. Cell Death Differ. 15:1153–1162. 2008. View Article : Google Scholar : PubMed/NCBI
66	Kim SH, Chen G, King AN, Jeon CK, Christensen PJ, Zhao L, Simpson RU, Thomas DG, Giordano TJ, Brenner DE, et al: Characterization of vitamin D receptor (VDR) in lung adenocarcinoma. Lung Cancer. 77:265–271. 2012. View Article : Google Scholar : PubMed/NCBI
67	Naves M, Alvarez-Hernández D, Fernández-Martín JL, Paz-Jiménez J, García-Prado P, Fernández-Coto T, Santamaría I and Cannata-Andía J: Effect of VDR gene polymorphisms on osteocalcin secretion in calcitriol-stimulated human osteoblasts. Kidney Int Suppl. 63:S23–S27. 2003. View Article : Google Scholar
68	Alvarez-Hernandez D, Naves-Diaz M, Gomez-Alonso C, Coto E and Cannata-Andia JB: Tissue-specific effect of VDR gene polymorphisms on the response to calcitriol. J Nephrol. 21:843–849. 2008.PubMed/NCBI
69	Dogan I, Onen HI, Yurdakul AS, Konac E, Ozturk C, Varol A and Ekmekci A: Polymorphisms in the vitamin D receptor gene and risk of lung cancer. Med Sci Monit. 15:BR232–BR242. 2009.PubMed/NCBI
70	Fu Y, Li J and Zhang Y: Polymorphisms in the vitamin D receptor gene and the lung cancer risk. Tumour Biol. 35:1323–1330. 2014. View Article : Google Scholar
71	Wu X, Cheng J and Yang K: Vitamin D-related gene polymorphisms, plasma 25-hydroxy-vitamin D, cigarette smoke and non-small cell lung cancer (NSCLC) risk. Int J Mol Sci. 17:202016. View Article : Google Scholar
72	Vaughan-Shaw PG, O'Sullivan F, Farrington SM, Theodoratou E, Campbell H, Dunlop MG and Zgaga L: The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: Systematic review and meta-analysis. Br J Cancer. 116:1092–1110. 2017. View Article : Google Scholar : PubMed/NCBI
73	Slominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, Wang J, Postlethwaite A, Li W, Tuckey RC, et al: RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J. 28:2775–2789. 2014. View Article : Google Scholar : PubMed/NCBI
74	Brożyna AA, Jóźwicki W, Skobowiat C, Jetten A and Slominski AT: RORα and RORγ expression inversely correlates with human melanoma progression. Oncotarget. 7:63261–63282. 2016. View Article : Google Scholar
75	Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, Li W, Tuckey RC and Jetten AM: Endogenously produced nonclassical vitamin D hydroxy-metabolites act as 'biased' agonists on VDR and inverse agonists on RORα and RORγ. J Steroid Biochem Mol Biol. 173:42–56. 2017. View Article : Google Scholar
76	Du J and Xu R: RORα, a potential tumor suppressor and therapeutic target of breast cancer. Int J Mol Sci. 13:15755–15766. 2012. View Article : Google Scholar
77	Slominski AT, Kim TK, Shehabi HZ, Semak I, Tang EKY, Nguyen MN, Benson HAE, Korik E, Janjetovic Z, Chen J, et al: In vivo evidence for a novel pathway of vitamin D-3 metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 26:3901–3915. 2012. View Article : Google Scholar : PubMed/NCBI
78	Slominski AT, Kim TK, Shehabi HZ, Tang EKY, Benson HAE, Semak I, Lin Z, Yates CR, Wang J, Li W, et al: In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes, Caco-2 colon cells and the adrenal gland. Mol Cell Endocrinol. 383:181–192. 2014. View Article : Google Scholar : PubMed/NCBI
79	Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EKY and Tuckey RC: Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland. Sci Rep. 5:148752015. View Article : Google Scholar : PubMed/NCBI
80	Slominski AT, Kim TK, Li W and Tuckey RC: Classical and non-classical metabolic transformation of vitamin D in dermal fibroblasts. Exp Dermatol. 25:231–232. 2016. View Article : Google Scholar :
81	Zhang Q, Kanterewicz B, Shoemaker S, Hu Q, Liu S, Atwood K and Hershberger P: Differential response to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in non-small cell lung cancer cells with distinct oncogene mutations. J Steroid Biochem Mol Biol. 136:264–270. 2013. View Article : Google Scholar
82	Mimori K, Tanaka Y, Yoshinaga K, Masuda T, Yamashita K, Okamoto M, Inoue H and Mori M: Clinical significance of the overexpression of the candidate oncogene CYP24 in esophageal cancer. Ann Oncol. 15:236–241. 2004. View Article : Google Scholar : PubMed/NCBI
83	Horváth HC, Lakatos P, Kósa JP, Bácsi K, Borka K, Bises G, Nittke T, Hershberger PA, Speer G and Kállay E: The candidate oncogene CYP24A1: A potential biomarker for colorectal tumorigenesis. J Histochem Cytochem. 58:277–285. 2010. View Article : Google Scholar :
84	Luo W, Hershberger PA, Trump DL and Johnson CS: 24-Hydroxylase in cancer: Impact on vitamin D-based anticancer therapeutics. J Steroid Biochem Mol Biol. 136:252–257. 2013. View Article : Google Scholar :
85	Zhang Q, Kanterewicz B, Buch S, Petkovich M, Parise R, Beumer J, Lin Y, Diergaarde B and Hershberger PA: CYP24 inhibition preserves 1α,25-dihydroxyvitamin D(3) anti-proliferative signaling in lung cancer cells. Mol Cell Endocrinol. 355:153–161. 2012. View Article : Google Scholar : PubMed/NCBI
86	Chung I, Yu WD, Karpf AR, Flynn G, Bernardi RJ, Modzelewski RA, Johnson CS and Trump DL: Anti-proliferative effects of calcitriol on endothelial cells derived from two different microenvironments. J Steroid Biochem Mol Biol. 103:768–770. 2007. View Article : Google Scholar : PubMed/NCBI
87	Spyridopoulos I, Brogi E, Kearney M, Sullivan AB, Cetrulo C, Isner JM and Losordo DW: Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: Balance between growth and death signals. J Mol Cell Cardiol. 29:1321–1330. 1997. View Article : Google Scholar : PubMed/NCBI
88	Aonuma M, Iwahana M, Nakayama Y, Hirotani K, Hattori C, Murakami K, Shibuya M and Tanaka NG: Tumorigenicity depends on angiogenic potential of tumor cells: Dominant role of vascular endothelial growth factor and/or fibroblast growth factors produced by tumor cells. Angiogenesis. 2:57–66. 1998. View Article : Google Scholar
89	Kieser A, Weich HA, Brandner G, Marmé D and Kolch W: Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene. 9:963–969. 1994.PubMed/NCBI
90	Mukhopadhyay D, Tsiokas L and Sukhatme VP: Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55:6161–6165. 1995.PubMed/NCBI
91	Niklińska W, Burzykowski T, Chyczewski L and Nikliński J: Expression of vascular endothelial growth factor (VEGF) in non-small cell lung cancer (NSCLC): Association with p53 gene mutation and prognosis. Lung Cancer. 34(Suppl 2): S59–S64. 2001. View Article : Google Scholar
92	Fontanini G, Boldrini L, Vignati S, Chinè S, Basolo F, Silvestri V, Lucchi M, Mussi A, Angeletti CA and Bevilacqua G: Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma. Eur J Cancer. 34:718–723. 1998. View Article : Google Scholar : PubMed/NCBI
93	Yuan A, Yu CJ, Luh KT, Kuo SH, Lee YC and Yang PC: Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer. J Clin Oncol. 20:900–910. 2002.PubMed/NCBI
94	Brown CJ, Lain S, Verma CS, Fersht AR and Lane DP: Awakening guardian angels: Drugging the p53 pathway. Nat Rev Cancer. 9:862–873. 2009. View Article : Google Scholar : PubMed/NCBI
95	Sundaram P, Dang CV and Thomas-Tikhonenko A: Myc and control of tumor neovascularization. Cancer Genome and Tumor Microenvironment. Thomas-Tikhonenko A: Springer; New York, NY: pp. 167–187. 2010, View Article : Google Scholar
96	Mahalingam D, Espitia CM, Medina EC, Esquivel JA II, Kelly KR, Bearss D, Choy G, Taverna P, Carew JS, Giles FJ, et al: Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma. Br J Cancer. 105:1563–1573. 2011. View Article : Google Scholar : PubMed/NCBI
97	Xie C, Pan Y, Hao F, Gao Y, Liu Z, Zhang X, Xie L, Jiang G, Li Q and Wang E: C-Myc participates in β-catenin-mediated drug resistance in A549/DDP lung adenocarcinoma cells. APMIS. 122:1251–1258. 2014. View Article : Google Scholar : PubMed/NCBI
98	O'Brate A and Giannakakou P: The importance of p53 location: Nuclear or cytoplasmic zip code? Drug Resist Updat. 6:313–322. 2003. View Article : Google Scholar
99	Levine AJ and Oren M: The first 30 years of p53: Growing ever more complex. Nat Rev Cancer. 9:749–758. 2009. View Article : Google Scholar : PubMed/NCBI
100	Patel S and Player MR: Small-molecule inhibitors of the p53-HDM2 interaction for the treatment of cancer. Expert Opin Investig Drugs. 17:1865–1882. 2008. View Article : Google Scholar : PubMed/NCBI
101	Panka DJ, Liu Q, Geissler AK and Mier JW: Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b⁺/Gr-1⁺ myeloid derived suppressor cells. Mol Cancer. 12:172013. View Article : Google Scholar
102	Gan L, Wang J, Xu H and Yang X: Resistance to docetaxel-induced apoptosis in prostate cancer cells by p38/p53/p21 signaling. Prostate. 71:1158–1166. 2011. View Article : Google Scholar : PubMed/NCBI
103	Kumagai T, O'Kelly J, Said JW and Koeffler HP: Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: Antitumor activity against leukemia, myeloma, and colon cancer cells. J Natl Cancer Inst. 95:896–905. 2003. View Article : Google Scholar : PubMed/NCBI
104	Ma J, Sawai H, Ochi N, Matsuo Y, Xu D, Yasuda A, Takahashi H, Wakasugi T and Takeyama H: PTEN regulates angiogenesis through PI3K/Akt/VEGF signaling pathway in human pancreatic cancer cells. Mol Cell Biochem. 331:161–171. 2009. View Article : Google Scholar : PubMed/NCBI
105	Clarke JM and Hurwitz HI: Understanding and targeting resistance to anti-angiogenic therapies. J Gastrointest Oncol. 4:253–263. 2013.PubMed/NCBI
106	Giuliano S and Pagès G: Mechanisms of resistance to anti-angiogenesis therapies. Biochimie. 95:1110–1119. 2013. View Article : Google Scholar : PubMed/NCBI
107	Joosten SC, Hamming L, Soetekouw PM, Aarts MJ, Veeck J, van Engeland M and Tjan-Heijnen VC: Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives. Biochim Biophys Acta. 1855:1–16. 2015.
108	Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA and Teh BT: Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 70:1063–1071. 2010. View Article : Google Scholar : PubMed/NCBI
109	Wysoczynski M, Shin DM, Kucia M and Ratajczak MZ: Selective upregulation of interleukin-8 by human rhabdomyosarcomas in response to hypoxia: Therapeutic implications. Int J Cancer. 126:371–381. 2010. View Article : Google Scholar
110	Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar
111	Chen W, Li Z, Bai L and Lin Y: NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Front Biosci (Landmark Ed). 16:1172–1185. 2011. View Article : Google Scholar
112	Sanchez A, Tripathy D, Yin X, Luo J, Martinez JM and Grammas P: Sunitinib enhances neuronal survival in vitro via NF-κB-mediated signaling and expression of cyclooxygenase-2 and inducible nitric oxide synthase. J Neuroinflammation. 10:932013. View Article : Google Scholar
113	Barkett M and Gilmore TD: Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene. 18:6910–6924. 1999. View Article : Google Scholar : PubMed/NCBI
114	Aoki M, Nata T, Morishita R, Matsushita H, Nakagami H, Yamamoto K, Yamazaki K, Nakabayashi M, Ogihara T and Kaneda Y: Endothelial apoptosis induced by oxidative stress through activation of NF-kappaB: Antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension. 38:48–55. 2001. View Article : Google Scholar : PubMed/NCBI
115	Royds JA, Dower SK, Qwarnstrom EE and Lewis CE: Response of tumour cells to hypoxia: Role of p53 and NFkB. Mol Pathol. 51:55–61. 1998. View Article : Google Scholar : PubMed/NCBI
116	Perkins ND and Gilmore TD: Good cop, bad cop: The different faces of NF-kappaB. Cell Death Differ. 13:759–772. 2006. View Article : Google Scholar : PubMed/NCBI
117	Krishnan AV and Feldman D: Molecular pathways mediating the anti-inflammatory effects of calcitriol: Implications for prostate cancer chemoprevention and treatment. Endocr Relat Cancer. 17:R19–R38. 2010. View Article : Google Scholar