(±)-Gossypol induces apoptosis and autophagy in head and neck carcinoma cell lines and inhibits the growth of transplanted salivary gland cancer cells in BALB/c mice

References

• Abou-Donia MB, Dieckert JW. 1975. Metabolic fate of gossypol: the metabolism of [14-C]gossypol in swine. Toxicol Appl Pharmacol. 31:32–46.
   PubMed Web of Science ®Google Scholar
• Andrews GA, Xi S, Pomerantz RG, Lin CJ, Gooding WE, Wentzel AL, Wu L, et al. 2004. Mutation of p53 in head and neck squamous cell carcinoma correlates with bcl-2 expression and increased susceptibility to cisplatin-induced apoptosis. Head Neck. 26:870–877.
   PubMed Web of Science ®Google Scholar
• Barth S, Glick D, Macleod KF. 2010. Autophagy: assays and artifacts. J Pathol. 221:117–124.
   PubMed Web of Science ®Google Scholar
• Bauer JA, Trask DK, Kumar B, Los G, Castro J, Lee JS, Chen J, et al. 2005. Reversal of cisplatin resistance with a BH3 mimetic, (−)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL. Mol Cancer Ther. 4:1096–1104.
   PubMed Web of Science ®Google Scholar
• Bei R, Guptill V, Masuelli L, Kashmiri SV, Muraro R, Frati L, Schlom J, Kantor J. 1998. The use of a cationic liposome formulation (DOTAP) mixed with a recombinant tumor-associated antigen to induce immune responses and protective immunity in mice. J Immunother. 21:159–169.
   PubMed Web of Science ®Google Scholar
• Bei R, Pompa G, Vitolo D, Moriconi E, Ciocci L, Quaranta M, Frati L, et al. 2001. Co-localization of multiple ErbB receptors in stratified epithelium of oral squamous cell carcinoma. J Pathol. 195:343–348.
   PubMed Web of Science ®Google Scholar
• Benvenuto M, Mattera R, Taffera G, Giganti MG, Lido P, Masuelli L, Modesti A, Bei R. 2016. The potential protective effects of polyphenols in asbestos-mediated inflammation and carcinogenesis of mesothelium. Nutrients. 8:pii:E275.
   PubMed Web of Science ®Google Scholar
• Benvenuto M, Sileri P, Rossi P, Masuelli L, Fantini M, Nanni M, Franceschilli L, et al. 2015. Natural humoral immune response to ribosomal P0 protein in colorectal cancer patients. J Transl Med. 13:101.
   PubMed Web of Science ®Google Scholar
• Boehm AL, Sen M, Seethala R, Gooding WE, Freilino M, Wong SM, Wang S, et al. 2008. Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck. Mol Pharmacol. 73:1632–1642.
   PubMed Web of Science ®Google Scholar
• Chang JS, Hsu YL, Kuo PL, Chiang LC, Lin CC. 2004. Upregulation of Fas/Fas ligand-mediated apoptosis by gossypol in an immortalized human alveolar lung cancer cell line. Clin Exp Pharmacol Physiol. 31:716–722.
   PubMed Web of Science ®Google Scholar
• Comel A, Sorrentino G, Capaci V, Del Sal G. 2014. The cytoplasmic side of p53’s oncosuppressive activities. FEBS Lett. 588:2600–2609.
   PubMed Web of Science ®Google Scholar
• Courtois SJ, Woodworth CD, Degreef H, Garmyn M. 1997. Early ultraviolet B-induced G1 arrest and suppression of the malignant phenotype by wild-type p53 in human squamous cell carcinoma cells. Exp Cell Res. 233:135–144.
   PubMed Web of Science ®Google Scholar
• Dao VT, Gaspard C, Mayer M, Werner GH, Nguyen SN, Michelot RJ. 2000. Synthesis and cytotoxicity of gossypol related compounds. Eur J Med Chem. 35:805–813.
   PubMed Web of Science ®Google Scholar
• Delbridge AR, Strasser A. 2015. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 22:1071–1080.
   PubMed Web of Science ®Google Scholar
• FAO/WHO/UNICEF. 1972. Protein Advisory Group of the United Nations, PAG Guideline No.4, “Preparation of Edible Cottonseed Protein Concentrate.” New York: FAO/WHO/UNICEF.
   Google Scholar
• Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, et al. 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386.
   PubMed Web of Science ®Google Scholar
• Flack MR, Pyle RG, Mullen NM, Lorenzo B, Wu YW, Knazek RA, Nisula BC, Reidenberg MM. 1993. Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab. 76:1019–1024.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration (FDA). 1974. Food drug cosmetic law. 56, 518.94, 172.894.
   Google Scholar
• Frajese GV, Benvenuto M, Fantini M, Ambrosin E, Sacchetti P, Masuelli L, Giganti MG, et al. 2016. Potassium increases the antitumor effects of ascorbic acid in breast cancer cell lines in vitro. Oncol Lett. 11:4224–4234.
   PubMed Web of Science ®Google Scholar
• Gao P, Bauvy C, Souquère S, Tonelli G, Liu L, Zhu Y, Qiao Z, et al. 2010. The Bcl-2 homology domain 3 mimetic gossypol induces both Beclin 1-dependent and Beclin 1-independent cytoprotective autophagy in cancer cells. J Biol Chem. 285:25570–25581.
   PubMed Web of Science ®Google Scholar
• Hata AN, Engelman JA, Faber AC. 2015. The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov. 5:475–487.
   PubMed Web of Science ®Google Scholar
• Hou DX, Uto T, Tong X, Takeshita T, Tanigawa S, Imamura I, Ose T, Fujii M. 2004. Involvement of reactive oxygen species-independent mitochondrial pathway in gossypol-induced apoptosis. Arch Biochem Biophys. 428:179–187.
   PubMed Web of Science ®Google Scholar
• Hron RJ, Kim HL, Calhoun MC, Fisher GS. 1999. Determination of (+)-, (−)-, and total gossypol in cottonseed by high-performance liquid chromatography. J Am Oil Chem Soc. 76:1351–1355.
   Web of Science ®Google Scholar
• Huang YW, Wang LS, Chang HL, Ye W, Sugimoto Y, Dowd MK, Wan PJ, Lin YC. 2006. Effects of serum on (−)-gossypol-suppressed growth in human prostate cancer cells. Anticancer Res. 26:3613–3620.
   PubMed Web of Science ®Google Scholar
• Imai A, Zeitlin BD, Visioli F, Dong Z, Zhang Z, Krishnamurthy S, Light E, et al. 2012. Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects. Cancer Res. 72:716–725.
   PubMed Web of Science ®Google Scholar
• Jiang J, Ye W, Lin YC. 2009. Gossypol inhibits the growth of MAT-LyLu prostate cancer cells by modulation of TGFbeta/Akt signaling. Int J Mol Med. 24:69–75.
   PubMed Web of Science ®Google Scholar
• Kang R, Zeh HJ, Lotze MT, Tang D. 2011. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 18:571–580.
   PubMed Web of Science ®Google Scholar
• Kim JS, Oh D, Yim MJ, Park JJ, Kang KR, Cho IA, Moon SM, et al. 2015. Berberine induces FasL-related apoptosis through p38 activation in KB human oral cancer cells. Oncol Rep. 33:1775–1782.
   PubMed Web of Science ®Google Scholar
• Kitada S, Kress CL, Krajewska M, Jia L, Pellecchia M, Reed JC. 2008. Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2-transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048). Blood. 111:3211–3219.
   PubMed Web of Science ®Google Scholar
• Ko CH, Shen SC, Yang LY, Lin CW, Chen YC. 2007. Gossypol reduction of tumor growth through ROS-dependent mitochondria pathway in human colorectal carcinoma cells. Int J Cancer. 121:1670–1679.
   PubMed Web of Science ®Google Scholar
• Li C, Johnson DE. 2012. Bortezomib induces autophagy in head and neck squamous cell carcinoma cells via JNK activation. Cancer Lett. 314:102–107.
   PubMed Web of Science ®Google Scholar
• Lian J, Karnak D, Xu L. 2010. The Bcl-2-Beclin 1 interaction in (−)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy. 6:1201–1203.
   PubMed Web of Science ®Google Scholar
• Lin J, Wu Y, Yang D, Zhao Y. 2013a. Induction of apoptosis and antitumor effects of a small molecule inhibitor of Bcl-2 and Bcl-xl, gossypol acetate, in multiple myeloma in vitro and in vivo. Oncol Rep. 30:731–738.
   PubMed Web of Science ®Google Scholar
• Lin YL, Yuksel Durmaz Y, Nör JE, El-Sayed ME. 2013b. Synergistic combination of small molecule inhibitor and RNA interference against antiapoptotic Bcl-2 protein in head and neck cancer cells. Mol Pharm. 10:2730–2738.
   PubMed Web of Science ®Google Scholar
• Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, Geneste O, Kroemer G. 2007. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy. 3:374–376.
   PubMed Web of Science ®Google Scholar
• Marquez RT, Liang X. 2012. Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res. 2:214–221.
   PubMed Web of Science ®Google Scholar
• Masuelli L, Bei R, Sacchetti P, Scappaticci I, Francalanci P, Albonici L, Coletti A, et al. 2003. Beta-catenin accumulates in intercalated disks of hypertrophic cardiomyopathic hearts. Cardiovasc Res. 60:376–387.
   PubMed Web of Science ®Google Scholar
• Masuelli L, Budillon A, Marzocchella L, Mrozek MA, Vitolo D, Di Gennaro E, Losito S, et al. 2012b. Caveolin-1 overexpression is associated with simultaneous abnormal expression of the E-cadherin/α-β catenins complex and multiple ErbB receptors and with lymph nodes metastasis in head and neck squamous cell carcinomas. J Cell Physiol. 227:3344–3353.
   PubMed Web of Science ®Google Scholar
• Masuelli L, Di Stefano E, Fantini M, Mattera R, Benvenuto M, Marzocchella L, Sacchetti P, et al. 2014a. Resveratrol potentiates the in vitro and in vivo anti-tumoral effects of curcumin in head and neck carcinomas. Oncotarget. 5:10745–10762.
   PubMed Web of Science ®Google Scholar
• Masuelli L, Fantini M, Benvenuto M, Sacchetti P, Giganti MG, Tresoldi I, Lido P, Lista F, Cavallo F, Nanni P, et al. 2014b. Intratumoral delivery of recombinant vaccinia virus encoding for ErbB2/Neu inhibits the growth of salivary gland carcinoma cells. J Transl Med. 12:122.
   PubMed Web of Science ®Google Scholar
• Masuelli L, Marzocchella L, Focaccetti C, Lista F, Nardi A, Scardino A, Mattei M, et al. 2010. Local delivery of recombinant vaccinia virus encoding for neu counteracts growth of mammary tumors more efficiently than systemic delivery in neu transgenic mice. Cancer Immunol Immunother. 59:1247–1258.
   PubMed Web of Science ®Google Scholar
• Masuelli L, Marzocchella L, Focaccetti C, Tresoldi I, Palumbo C, Izzi V, Benvenuto M, et al. 2012a. Resveratrol and diallyl disulfide enhance curcumin-induced sarcoma cell apoptosis. Front Biosci. 17:498–508.
   PubMed Web of Science ®Google Scholar
• Masuelli L, Pantanella F, La Regina G, Benvenuto M, Fantini M, Mattera R, Di Stefano E, et al. 2016. Violacein, an indole-derived purple-colored natural pigment produced by Janthinobacterium lividum, inhibits the growth of head and neck carcinoma cell lines both in vitro and in vivo. Tumour Biol. 37:3705–3717.
   PubMed Web of Science ®Google Scholar
• Meng Y, Tang W, Dai Y, Wu X, Liu M, Ji Q, Ji M, et al. 2008. Natural BH3 mimetic (−)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol Cancer Ther. 7:2192–2202.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Yoshimori T. 2007. How to interpret LC3 immunoblotting. Autophagy. 3:542–545.
   PubMed Web of Science ®Google Scholar
• Oliver CL, Bauer JA, Wolter KG, Ubell ML, Narayan A, O’Connell KM, Fisher SG, et al. 2004. In vitro effects of the BH3 mimetic, (−)-gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res. 10:7757–7763.
   PubMed Web of Science ®Google Scholar
• Pang X, Wu Y, Wu Y, Lu B, Chen J, Wang J, Yi Z, et al. 2011. (−)-Gossypol suppresses the growth of human prostate cancer xenografts via modulating VEGF signaling-mediated angiogenesis. Mol Cancer Ther. 10:795–805.
   PubMed Web of Science ®Google Scholar
• Pannellini T, Spadaro M, Di Carlo E, Ambrosino E, Iezzi M, Amici A, Lollini PL, et al. 2006. Timely DNA vaccine combined with systemic IL-12 prevents parotid carcinomas before a dominant-negative p53 makes their growth independent of HER-2/neu expression. J Immunol. 176:7695–7703.
   PubMed Web of Science ®Google Scholar
• Park MR, Kim SG, Cho IA, Oh D, Kang KR, Lee SY, Moon SM, et al. 2015. Licochalcone-A induces intrinsic and extrinsic apoptosis via ERK1/2 and p38 phosphorylation-mediated TRAIL expression in head and neck squamous carcinoma FaDu cells. Food Chem Toxicol. 77:34–43.
   PubMed Web of Science ®Google Scholar
• Reiss M, Brash DE, Muñoz-Antonia T, Simon JA, Ziegler A, Vellucci VF, Zhou ZL. 1992. Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines. Oncol Res. 4:349–357.
   PubMed Web of Science ®Google Scholar
• Roberts PJ, Der CJ. 2007. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 26:3291–3310.
   PubMed Web of Science ®Google Scholar
• Sacco AG, Worden FP. 2016. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. Onco Targets Ther. 9:1927–1943.
   PubMed Web of Science ®Google Scholar
• Sadahira K, Sagawa M, Nakazato T, Uchida H, Ikeda Y, Okamoto S, Nakajima H, Kizaki M. 2014. Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway. Int J Oncol. 45:2278–2286.
   PubMed Web of Science ®Google Scholar
• Saleem A, Dvorzhinski D, Santanam U, Mathew R, Bray K, Stein M, White E, DiPaola RS. 2012. Effect of dual inhibition of apoptosis and autophagy in prostate cancer. Prostate. 72:1374–1381.
   PubMed Web of Science ®Google Scholar
• Santana AT, Guelfi M, Medeiros HC, Tavares MA, Bizerra PF, Mingatto FE. 2015. Mechanisms involved in reproductive damage caused by gossypol in rats and protective effects of vitamin E. Biol Res. 48:43.
   PubMed Web of Science ®Google Scholar
• Schelman WR, Mohammed TA, Traynor AM, Kolesar JM, Marnocha RM, Eickhoff J, Keppen M, et al. 2014. A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer. Invest New Drugs. 32:295–302.
   PubMed Web of Science ®Google Scholar
• Shelley MD, Hartley L, Fish RG, Groundwater P, Morgan JJ, Mort D, Mason M, Evans A. 1999. Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines. Cancer Lett. 135:171–180.
   PubMed Web of Science ®Google Scholar
• Sinha S, Levine B. 2008. The autophagy effector Beclin 1. A novel BH3-only protein. Oncogene. 27:S137–S148.
   Web of Science ®Google Scholar
• Sonpavde G, Matveev V, Burke JM, Caton JR, Fleming MT, Hutson TE, Galsky MD, et al. 2012. Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann Oncol. 23:1803–1808.
   PubMed Web of Science ®Google Scholar
• Stein RC, Joseph AE, Matlin S, Cunningham DC, Ford HT, Coombes RC. 1992. A preliminary clinical study of gossypol in advanced human cancer. Cancer Chemother Pharmacol. 30:480–482.
   PubMed Web of Science ®Google Scholar
• Sunilkumar G, Campbell LM, Puckhaber L, Stipanovic RD, Rathore KS. 2006. Engineering cottonseed for use in human nutrition by tissue-specific reduction of toxic gossypol. Proc Natl Acad Sci USA. 103:18054–18059.
   PubMed Web of Science ®Google Scholar
• Swiecicki PL, Bellile E, Sacco AG, Pearson AT, Taylor JM, Jackson TL, Chepeha DB, et al. 2016. A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. Invest New Drugs. 34:481–489.
   PubMed Web of Science ®Google Scholar
• van Poznak C, Seidman AD, Reidenberg MM, Moasser MM, Sklarin N, Van Zee K, Borgen P, et al. 2001. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res Treat. 66:239–248.
   PubMed Web of Science ®Google Scholar
• Vela L, Gonzalo O, Naval J, Marzo I. 2013. Direct interaction of Bax and Bak proteins with Bcl-2 homology domain 3 (BH3)-only proteins in living cells revealed by fluorescence complementation. J Biol Chem. 288:4935–4946.
   PubMed Web of Science ®Google Scholar
• Wada T, Penninger JM. 2004. Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 23:2838–2849.
   PubMed Web of Science ®Google Scholar
• Wang J, Peng Y, Liu Y, Yang J, Huang M, Tan W. 2015. AT-101 inhibits hedgehog pathway activity and cancer growth. Cancer Chemother Pharmacol. 76:461–469.
   PubMed Web of Science ®Google Scholar
• Wang X, Howell CP, Chen F, Yin J, Jiang Y. 2009. Gossypol-a polyphenolic compound from cotton plant. Adv Food Nutr Res. 58:215–263.
   PubMedGoogle Scholar
• Wang X, Wang J, Wong SC, Chow LS, Nicholls JM, Wong YC, Liu Y, et al. 2000. Cytotoxic effect of gossypol on colon carcinoma cells. Life Sci. 67:2663–2671.
   PubMed Web of Science ®Google Scholar
• Wolter KG, Wang SJ, Henson BS, Wang S, Griffith KA, Kumar B, Chen J, et al. 2006. (−)-Gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo. Neoplasia. 8:163–172.
   PubMed Web of Science ®Google Scholar
• Xie X, Clausen OP, De Angelis P, Boysen M. 1999. The prognostic value of spontaneous apoptosis, Bax, bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer. 86:913–920.
   PubMed Web of Science ®Google Scholar
• Xu L, Yang D, Wang S, Tang W, Liu M, Davis M, Chen J, et al. 2005. (−)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. Mol Cancer Ther. 4:197–205.
   PubMed Web of Science ®Google Scholar
• Yin J, Jin L, Chen F, Wang X, Kitaygorodskiy A, Jiang Y. 2011. Novel O-glycosidic gossypol isomers and their bioactivities. Carbohydr Res. 346:2070–2074.
   PubMed Web of Science ®Google Scholar
• Yu Y, Dong W, Li X, Yu E, Zhou X, Li S. 2003. Significance of c-Myc and Bcl-2 protein expression in nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 129:1322–1326.
   PubMedGoogle Scholar
• Zhang M, Liu H, Guo R, Ling Y, Wu X, Li B, Roller PP, et al. 2003. Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. Biochem Pharmacol. 66:93–103.
   PubMed Web of Science ®Google Scholar
• Zhang XQ, Huang XF, Mu SJ, An QX, Xia AJ, Chen R, Wu DC. 2010. Inhibition of proliferation of prostate cancer cell line, PC-3, in vitro and in vivo using (–)-gossypol. Asian J Androl. 12:390–399.
   PubMed Web of Science ®Google Scholar
• Zhao GX, Xu LH, Pan H, Lin QR, Huang MY, Cai JY, Ouyang DY, He XH. 2015. The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling. Oncotarget. 6:38952–38966.
   PubMed Web of Science ®Google Scholar
• Zerp SF, Stoter R, Kuipers G, Yang D, Lippman ME, van Blitterswijk WJ, Bartelink H, et al. 2009. AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis. Radiat Oncol. 4:47.
   PubMed Web of Science ®Google Scholar