Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma.

Constitutive activation of nuclear factor erythroid 2-related factor 2 (NRF2) is pivotal in bestowing therapy resistance in cancer cells. Several phytochemicals have been reported with the potential of modulating NRF2. Therefore, it was hypothesized that NRF2-deregulated chemoresistance in lung adenocarcinoma (LUAD) may be counteracted by theaflavin-rich black tea (BT). A non-responsive LUAD cell line, A549, was the best sensitized towards cisplatin upon pre-treatment with BT. BT-mediated NRF2 reorientation was observed to be dependent on concentration and duration of treatment as well as on the mutational profile of NRF2 in A549 cells. Transient exposure of low-concentration BT hormetically downregulated NRF2, its downstream antioxidants, and drug transporter. BT also influenced the Kelch-like ECH-associated protein (KEAP1)-dependent cullin 3 (Cul3) and KEAP-1-independent signaling through epidermal growth factor receptor (EGFR) - rat sarcoma virus (RAS) - rapidly accelerated fibrosarcoma (RAF) - extracellular signal-regulated kinase 1/2 (ERK) - matrix metalloproteinase (MMP)-2 and MMP-9. The realignment of NRF2 in KEAP1-suppressed A549 cells enhanced the chemotherapeutic outcome. But a higher concentration of the same BT surprisingly upregulated NRF2 and its transcriptional targets with a subsequent decrease in the NRF2-regulatory machinery in NCI-H23 cells (a KEAP1-overexpressed LUAD cell line), ultimately resulting in a better anticancer response. The BT-mediated bidirectional NRF2 modulation was reconfirmed upon comparison with the action of a pharmacological NRF2 inhibitor, ML-385, in A549 and a known NRF2 activator, tertiary-butylhydroquinone, in NCI-H23 respectively. BT-mediated regulation of NRF2-KEAP1 and their upstream networks (EGFR/RAS/RAF/ERK) sufficed as a better anticancer agent than synthetic NRF2 modulators. Therefore, BT may be indicated as a potent multi-modal small molecule for increasing drug responsiveness in LUAD cells by maintaining NRF2/KEAP1 axis at an optimum level.

Flexion of Nrf2 by tea phytochemicals: A review on the chemopreventive and chemotherapeutic implications.

Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2), the redox-sensitive transcription factor, plays a key role in stress-defense and detoxification. Nrf2 is tightly controlled by its negative regulator cum sensor Kelch-[ECH]-associated protein 1 (Keap1). Nrf2 is well known for its dual nature owing to its cancer preventive and cancer promoting abilities. Modulation of this biphasic nature of Nrf2 signaling by phytochemicals may be a potential cancer preventive and anticancer therapeutic strategy. Phytocompounds may either act as Nrf2-activator or Nrf2-inhibitor depending on their differential concentration and varied cellular environment. Tea is not just the most popular global beverage with innumerable health-benefits but has well-established chemopreventive and chemotherapeutic effects. Various types of tea infusions contain a wide range of bioactive compounds, such as polyphenolic catechins and flavonols, which are endowed with potent antioxidant properties. Despite of their rapid biotransformation and poor bioavailability, regular tea consumption is risk-reductive for several cancer forms. Tea catechins show their dual Nrf2-modulatory effect by directly acting on Nrf2-Keap1 or their upstream regulators and downstream effectors in a highly case-specific manner. In this review, we have tried to present a comprehensive evaluation of the Nrf2-mediated chemopreventive and chemotherapeutic applications of tea in various preclinical cancer models, the Nrf2-modulatory mechanisms, and the limitations which need to be addressed in future research.

Low dose epigallocatechin-3-gallate revives doxorubicin responsiveness by a redox-sensitive pathway in A549 lung adenocarcinoma cells.

Pulmonary cancer confronts the greatest hurdle of resistance against most chemotherapeutic drugs. This may be circumvented with a combination of conventional chemotherapy with bioactive herbal adjuvant. Epigallocatechin-3-gallate (EGCG), was investigated for its chemo-sensitizing property along with doxorubicin (Dox), in an intrinsically nonresponsive lung adenocarcinoma (LAC) cell line, A549. A compromised functionality of Dox was reversed when EGCG was used as an adjuvant. On one hand, Dox (10 µM)-EGCG (0.5 µM) post treatment combination decreased the drug efflux, multidrug-resistance (MDR) signaling, invasiveness while, on the other hand, it increased drug internalization, cell-cycle arrest, stress-induced damage, and finally cell death. The resistant nature of A549 was probably due to constitutive activation of nuclear erythroid 2-related factor 2 (Nrf2) and its upstream/downstream antioxidant effectors, which were also pro-oxidatively coordinated by EGCG. In conclusion low dose EGCG improved Dox-toxicity and imparted oxidative damage-mediated antineoplastic efficacy by reorienting the redox signaling in A549 LAC cells.

Bioengineering of Extracellular Vesicles: Exosome-Based Next-Generation Therapeutic Strategy in Cancer.

Extracellular nano vesicles and exosomes hold compelling evidence in intercellular communication. Exosomal intracellular signal transduction is mediated by the transfer of cargo proteins, lipids, micro (mi)RNAs, long noncoding (lnc)RNAs, small interfering (si)RNAs, DNA, and other functional molecules that play a pivotal role in regulating tumor growth and metastasis. However, emerging research trends indicate that exosomes may be used as a promising tool in anticancer treatment. This review features a majority of the bioengineering applications of fabricated exosomal cargoes. It also encompasses how the manipulation and delivery of specific cargoes-noncoding RNAs (ncRNAs), recombinant proteins, immune-modulators, chemotherapeutic drugs, and other small molecules-may serve as a precise therapeutic approach in cancer management.