The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer.
Thymoquinone (TQ) is the active ingredient of Nigella sativa which has a therapeutic potential in cancer therapy and prevention. In this study, TQ has been shown to induce specific cytotoxicity and apoptosis and to inhibit wound healing in triple-negative breast cancer cell line. TQ also inhibited cancer growth in a mouse tumor model. Moreover, TQ and paclitaxel (Pac) combination inhibited cancer growth in cell culture and in mice. Genes involved in TQ and TQ-Pac-mediated cytotoxicity were studied using focused real-time PCR arrays. After bioinformatic analysis, genes in apoptosis, cytokine, and p53 signaling categories were found to be modulated with a high significance in TQ-treated cells (p < 10(-28), p < 10(-8), and p < 10(-6), respectively). Important to note, TQ has been found to regulate the genes involved in the induction of apoptosis through death receptors (p = 5.5 × 10(-5)). Additionally, tumor suppressor genes such as p21, Brca1, and Hic1 were highly upregulated by TQ and TQ-Pac combination. Interestingly, when cells were treated with high dose TQ, several growth factors such as Vegf and Egf were upregulated and several pro-apoptotic factors such as caspases were downregulated possibly pointing out key pathways manipulated by cancer cells to resist against TQ. In cells treated with the combination of TQ and Pac, genes in apoptosis cascade (p < 10(-12)), p53 signaling (p = 10(-5)), and JAK-STAT signaling (p < 10(-3)) were differentially expressed. TQ has also been shown to induce protein levels of cleaved Caspase-3, Caspase-7, and Caspase-12 and PARP and to reduce phosphorylated p65 and Akt1. The in vivo therapeutic potential of TQ-Pac combination and the genetic network involved in this synergy have been shown for the first time to the best of our knowledge.
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey. sakalar11@hotmail.com.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey. sakalar11@hotmail.com.
Çağrı
Ç
Şakalar
Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.|Department of Medical Biochemistry, School of Medicine, Erciyes University, Melikgazi, Kayseri, Turkey.
Kenan
K
İzgi
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.
Banu
B
İskender
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.
Sedat
S
Sezen
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.
Huriye
H
Aksu
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.
Mustafa
M
Çakır
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.
Büşra
B
Kurt
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.
Ali
A
Turan
Department of Medical Biology, School of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.|Genome and Stem Cell Center, Erciyes University, Melikgazi, Kayseri, Turkey.
Halit
H
Canatan
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016227:Benzoquinones / Q000008:administration & dosage; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; C003466:thymoquinone; D017239:Paclitaxel
Breast cancer; Gene expression profile; In vivo; Intrinsic and extrinsic apoptosis axis; Paclitaxel; Synergy; Thymoquinone; p53 signaling