Overcoming multifaceted challenges in cancer treatment: Targeting signal transduction pathways and tumor microenvironment for enhanced therapeutic efficacy

INTRODUCTION

The complexity of cancer has provided both researchers and healthcare professionals with a significant opportunity to advance understanding and treatment. Across various classifications, cancer remains a leading cause of death worldwide [1], despite the implementation of multiple therapeutic approaches. One of the most daunting challenges lies in the intricate etiology of cancer, particularly as it progresses to advanced stages. The widely accepted tumor node metastasis staging system underscores the complexity of cancer diagnosis and treatment planning. While early-stage tumors may be effectively managed through surgical interventions, the presence of metastasis necessitates a combination of adjuvant chemo radiation and surgical modalities. However, the success rates of these interventions remain dishearteningly low, largely due to the aggressive nature of metastatic cancer, which can infiltrate and affect multiple organs in various ways. Chemo radiation therapy, in NSCLC, paclitaxel in chemotherapy with radiation, and oxaliplatin in chemotherapy with radiation although integral to cancer treatment, often fall short of fully addressing metastatic cancer. Consequently, chemotherapy emerges as a cornerstone modality in the management of metastasized cancer. However, the emergence of chemotherapeutic drug resistance poses a significant hurdle to achieving successful treatment outcomes [2].

In recent years, the development of novel drug candidates utilizing sophisticated drug design approaches and considering explicit clinical parameters has shown promise. Despite these advancements, the persistence of chemotherapy resistance highlights the ongoing challenge of achieving a comprehensive cure for cancer. In navigating this landscape, it is crucial to delve deeper into the mechanisms driving cancer progression and treatment resistance. By embracing a multifaceted approach that combines innovative therapeutic modalities with a nuanced understanding of cancer biology, we can strive towards more effective treatment strategies and improved outcomes for patients battling this formidable disease.

Approaches on the robust basis of physiology via killing cancerous cells by oxidized free radicals and reactive oxygen species (ROS) in cells. The study revealed platinum class alkylating chemotherapeutic drug generated free radicals in cells that accept and transfer electrons oxygen and kill cancerous cells [1]. Cell organelle has a vital role involving mitochondria, endoplasmic reticulum, lysosomes, and Golgi bodies. Mitochondria and HIF have a strong interconnection in regulating cell death. Subdue mitochondrial function by HIF to participate in drug treatment failure [2].

The Otto Warburg illustrates damaged respiration and excessive fermentation in cells responsible for Cancer [3,4]. The D.N.A. of cell damage by ultra violet radiation. Carcinogens consequently defect in apoptosis liable for tumorigenesis [5]. Apoptosis of damaged D.N.A. control by (Ataxia telangiectasis mutated and RAD3 related) A.T.R./Chk-1 but mechanism not yet well established [6,7]. Evidently, upon D.N.A. damage by U.V. simultaneously activation of (Ataxia telangiectasis mutated) A.T.M./Chk-1 signaling pathway consequently down-regulates Smurf-1 and increases Rho-B consequently, apoptosis [8–10]. Failures are considered as an opportunity to be emphasized in this article. Multiple transduction pathways are to be found, analyzed, and then designed for chemotherapy. Among all other protein kinases, the most acceptable pathway is still a significant impediment in clinical oncology. Protein kinase involves receptor and non-receptor tyrosine kinase, Serine and threonine kinase, and other associated pathways. All signal transduction pathways majorly inhibit translation by altered transcription and replication whereas this perspective emphasizes hypoxia and immunotherapy. Another, parameter, tumor microenvironment (TME), was altered drug penetration due to adverse pharmacokinetic conditions consequently, promote tumor growth. Stromal cells in T.M.E. participate in uncontrolled proliferation, angiogenesis, and metastasis with drug impediments [11–18]. Tumor cells participate in hypoxia in the TME and its major impediment to cancer drugs [12]. Hypoxia participates by HIF-α and acidic TME. In hypoxic conditions, the fast proliferation of cancerous cells due to creates new angiogenic vasculature that contributes to delivering oxygenated blood [19,20]. The slowly proliferating cancer cells, under hypoxic conditions, escape from chemotherapy drugs, and these cancer cells ensure epithelial to mesenchymal transition. Some studies revealed in the acidic environment of cells lysosomes and endosomes in tumor cells support metastasis by activating protease [21,22]. The degradation of tumor cells in a neutral environment and simultaneously, improved by cytotoxic T lymphocyte, immunotherapy [23]. In the light of above point, hypoxia alters apoptosis cell death, autophagy to remove dead from cells, and immunotherapy to manage cancer.

Hypoxia modulation to manage Cancer

Hypoxia is to be considered as targeted for cancer therapy. Multiple ways to target hypoxic tumors are hypoxia-activated prodrug [40], hypoxia-inducible factor 1-alpha (HIF-1α) modulator, Prolyl 4-hydroxylase alpha-1 (P4HA1), Prolyl hydroxylase domain 2, Gene therapy, specific target pathways critical in hypoxia such as mTOR (mammalian target of rapamycin), unfolding protein response (UPR) pathways, Acid induced tumor. HIF-1α induced chemotherapeutic resistance in pancreatic cancer via up-regulation of cytidine triphosphate synthase and transketolase while using digoxigenin to halt HIF-1α induced translation. Consequently, encouraging results of gemcitabine in pancreatic Cancer [41–43].P4HA1 up regulated by HIF-1α in the TME of breast cancer. P4HA1 regulates cell metabolism and enhances tumors; thus, P4HA1 is a prominent target for breast cancer [41]. HIF-1α regulates the transcriptional regulation by gene TFP1 in breast cancer. Another prominent target of HIF-1α is prolyl hydroxylase domain 2 (PHD2) for breast cancer treatment. The hypoxia is further illustrated in Figure 1.

Figure 1. The figure depicts the effects of hypoxia on cellular and physiological processes. Hypoxia leads to the activation of HIF-1αsss, which results in mitochondrial dysfunction, p53 dysfunction, DNA damage, and autophagy. Additionally, hypoxia causes a decrease in pH, creating an acidic environment that contributes to immunity dysfunction, alteration of the TME, and increased drug resistance. This interplay highlights the critical role of hypoxia and HIF-1 in tumor progression and resistance to therapy. [Click here to view]

The hypoxic prodrug was activated by cellular reductase, re-oxidized into initial drug progenitors in anorexic cells, and then converted into a cytotoxic substance. Clinical trial phase-II results encourage hypoxic progenitor TH-302 with gemcitabine. Hypoxic agents as progenitors, also known as alkylating agents, are in Figure 2. TH-302 ((1) Evofosfamide) chemical class of alkylating agent and, in combination with (2) gemcitabine, synergistic action in pancreatic cancer [44]. Synergistic action of (3) praziquantel use as an adjunct therapy in bladder cancer with (4) Mitomycin-derived prodrug [45].

Figure 2. Hypoxic prodrugs. [Click here to view]

m-TOR pathway

The elevated level of m-TORC1 was detected in rodents and human tumors. Further, confirmed in tumor-derived cell lines have knockdown of TSC1:TSC2 [56–67]. Cell growth is regulated by the mTOR pathway involved, specifically by m-TORC1 upregulating and downregulating the TSC1/TSC2 complex. Other factors regulate cell growth by activating the m-TOR pathway and rising level A.M.P. consequently activated AMP kinase (AMPK) in multiple ways among one genotoxic stress by P-53 mediated activation. The mTORC1 activity is upregulated by growth factors through insulin or insulin-like growth factors, phosphoinositide-3’ kinase, A.K.T. pathway, Wnt-GSK3 signaling pathway and ERK-RSK kinase cascade [68,69].

m TORC1 activity modulates in adverse conditions, nutrient limitation, Hypoxia, and DNA damage disrupt the cell cycle and P53 signal. m TORC1 activity upregulates and downregulates by TSC1:TSC2 complex via GAP (GTPase activating protein) by action of GTPase-Rheb that stimulates mTORC1. m TOR regulation involves specifically sestrin-2 due to a decrease in GTP level. TSC activity also regulated by other kinase AKT, ERK, RSK, AMPK [70,71].

In stressed conditions, P53 precisely targets gene p21waf to activate sestrin, which means sestrin-1(PA26) and sestrin-2(Hi95) dimer interact with TSC1:TSC2 (Hamartin:tuberin) complex and phosphorylation by AMP induced AMPK-α consequently autophosphorylation TSC1:TSC2 complex simultaneously GAP activity by Rap1 induced by TSC2 and another factor Guanidine exchange factor also participate support by transitional controlled tumor protein study in drosophila [72] and m-TOR inhibition [73]. In cancer conditions, G.A.P. mutates, mTORC1 activation, and cell growth. m TOR proteins are serine-threonine kinase that belongs to the family of the phosphoinositide 3 kinase-related kinase and occurs in eukaryotes. m TOR occurs in two complex forms: mTORC1 and mTORC2. mTORC1 evidently participates in cancer, neurodegeneration while mTORC2 function is still not fully understood [74–77]. The m-TOR activity is illustrated in Figure 3 [78].

m TORC1 modulation was TSC complex-dependent signaling. TSC suppresses tumor cells and downregulates by phosphorylation. m-TORC1 upregulates cell growth, but the mTOR pathway still needs further research. m-TOR inhibitors (5), (6), (7), and (8) are in Figure 4. TSC complex downregulates by phosphorylation among GSK-3β, energy stress, and hypoxia to AMP activates AMPK, and hypoxia to HIF1α activates REDD1. In contrast, on the other side, hypoxia-induced HIF1α inhibited by Von Hippel-Lindau tumor suppressor furthermore WNT pathway inhibits GSK-3β to phosphorylation [79–88].

Figure 3. The figure illustrates the complex signaling pathways involving the mammalian target of rapamycin (mTOR), focusing on its two complexes: mTORC1 and mTORC2. mTORC1 is regulated by nutrients, growth factors, and energy status, promoting protein synthesis, lipogenesis, and ribosome biogenesis while inhibiting autophagy. Key regulators include Rheb-GTP, FKBP38, TSC1/TSC2, PI3K, AKT, and AMPK. mTORC2 mainly regulates cytoskeletal organization and cell survival through AKT, SGK, and PKC. The figure also highlights the downstream effects of mTOR activation, such as translation promotion via S6K and 4EBP1, and autophagy regulation through ULK1 and Beclin1. This interplay underscores the importance of mTOR in cellular growth, metabolism, and survival, pointing to potential therapeutic targets for diseases like cancer. [Click here to view]

Figure 4. mTOR modulator. [Click here to view]

Immunotherapy and Cancer

In cancer few decades, immunotherapy is illustrated in Figure 5 as one option to combat cancer [89–91]. Immunotherapy boosts immunity to kill cancer cells at checkpoints via checkpoint inhibitors, adoptive cell transfer, and vaccines. The increased immunity combat cancer cells via several checkpoint inhibitors among Cytotoxic T- lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and other renowned checkpoint inhibitor monoclonal antibodies (mAB) with the disadvantage of administration schedule, time-consuming procedure and costly and toxic effects not to be altered by any way in comparison to small drug molecule. The small drug molecule can reach the target site in the TME and low immunogenicity [92]. Find out small molecules that work in the TMEt and modulate immune suppression via either activating innate immune response or adaptive immune signaling pathway to treat Cancer. Among adenosine receptor signaling at immune checkpoint prominent target. Adenosine A_2AR and A_2BR receptor antagonists were used for cancer management by immune-modulation. The human immune system combats pathogens by way of inflammatory response. Tumors hijack and take control of the immune system, grow, and then metastasize [93]. The immune checkpoint pathways PD1, CTLA-4, A_2AR ,A_2BR, TIM-3(T cell immunoglobin and mucin domain-3) [94,95]. In normal physiological conditions, the level of adenosine is less than 1 µM [96] but observed adenosine levels (10 µM) in the TME and related pathological conditions are, as Cancer related fibroblasts, regulatory T cells, myeloid-derived suppressor cells (MDSCs), endothelial cells and T helper cells [97–103].

Figure 5. The diagram illustrates the interaction between adenosine and caffeine with the adenosine receptor. Adenosine acts as an agonist, binding to the adenosine receptor, leading to an increase in cAMP kinase activity. This cascade results in immunosuppression and the promotion of tumor proliferation. Conversely, caffeine functions as an antagonist to the adenosine receptor, potentially disrupting this pathway. The overall theme is the impact of small molecules on immunity and cellular processes. [Click here to view]

Upon binding adenosine to A_2AR and A_2BR to increase c AMP protein kinase, the signal is associated with the immune system and consequently, immunosuppressant in the TME. Increased intracellular c AMP level in T cells due to activation of A_2AR and A_2BR receptor consequently, decreased Tumor necrosis factor (TNFα), interleukin 2, and interferon Gamma, and compromised CD-8+ T cell infiltration [104–106]. Adenosine 2A receptor activation on regulatory T cells increases PD-1 and CTLA-4 expression, and macrophages promote tumor cell proliferation and increase immunosuppressant [107,108]. A_2BR alters cell differentiation by the mononuclear-phagocyte system, consequently, cancer angiogenesis, tumor spread, and suppression of lymphocyte-mediated anti-tumor immunity [109]. Thus, Adenosine receptor antagonist, PD1, CTLA-4, a prominent oncotarget. Evidently, in some studies alone, A_2AR antagonists were not encouraged as a result in CL8-1 melanoma cell line and RMA T cell lymphoma cell line exhibits dependent on CD8+ T cell activity but prominent observation metastasis decrease. The union of A_2AR and A_2BR antagonists with inhibition of PD-1 and CTLA-4 results in a prominent anticancer effect [110,111]. The A_2BR inhibition has prominent anti-tumor effects in prostate cancer, slow growth of the bladder, and breast cancer with decreased cell proliferation. Furthermore, it decreases tumor growth and immune suppression due to MDSCs and inhibits vascular endothelial growth factor and angiogenesis [112–115].

Adenosine antagonist for cancer immunotherapy

Adenosine 2A receptors have significance in cancer immunotherapy such as pyrazole and pyrimidine core. That article emphasizes anti-tumor effects concerning immunity. Natural and synthetic analogs as Adenosine receptor antagonists are Xanthine and analogue, Pyrimidine analogue, Azolopyrimidine analogues, Triazolo pyrimidine analogues, 2-oxothiazole analogue, Pyrazole and Benzothiazole analogue, Benzimidazole, Benzothiazole, Quinoxalines, Amino Pyrimidines, Triazine isomers, Pyrazole linked heterocyclics and miscellaneous as illustrated in Table 1.

Table 1. Synthetic analogues for cancer. [Click here to view]

Xanthine and its analogue

Xanthine and semi-synthetic analogues are illustrated in Figure 6. (9) Caffeine is a non-specific naturally occurring adenosine receptor antagonist (10) Istradefylline, a semi-synthetic xanthine analogue, have adenosine antagonist action and was initially designed to treat Parkinsonism, but (10) has revealed good result in Cancer [116] thus, as an option to repurpose for Cancer. Xanthine analogues have poor water solubility. Pyrazolo triazole Pyrimidine analogue non-xanthine adenosine 2A receptor antagonists are SCH58261, FSTP, ZM241385, and Tozadenant [117,118] (11). SCH58261 revealed the slowdown of metastasis in breast cancer by CD73 endogenously, and melanomas activate Nk cells (12). FSTP irreversible type antagonist and low efficacy due to impaired CD+ T cell differentiation and accumulation [119], (13) ZM241385 has poor solubility but inhibits lung cancer tumor metastasis [110], (14) Tozadenant enters clinical trial phase-3, but adverse events and scientists were further studies but encouraging results in breast cancer in combination with PD-1 inhibitors and mAB [105].

Figure 6. Xanthine and Pyrazolo triazole pyrimidine inhibitor. [Click here to view]

Pyrimidine analoguesAdoRx therapeutics design and patented pyrimidine derivatives are illustrated in Figure 7 as potent A_2AR and A_2BR antagonists. The 2-amino pyrimidine core chemical structure of the antagonist is A at R¹ position furan ring and at X-R² position aryl methylamine. These analogue (15), (16), (17), and (18) exhibit responses in lipopolysaccharide mediate TNFα release NECA reversal assay.

Figure 7. Pyrimidine inhibitors. [Click here to view]

Azolopyrimidine analogues

Arcus bioscience design and patented azolopyrimidine illustrated in Figure 8 to target Cancer [120] as an adenosine antagonist. In structure B at R⁴ position, substitution with methyl group activity decreases compared to hydrogen. Compound (19) exhibits A_2A receptor antagonist activity in CHO-TREx cAMP assay. Compound (20) have methyl benzonitrile and dose 100 mg/kg, po, b.i.d alone [121] or in combination with anti-PD-1 (5 mg/kg) or doxorubicin(6 mg/kg), consequently anti-tumor effects on B16-F-10 melanoma [122]. Arcus further two patents, one on quinazoline pyridine as compound C and its analogues (21), (22). Another quinazoline pyrazole core compound D and its analogue (23), (24). These compounds exhibit antagonist activity as A_2AR and A_2BR

Figure 8. Azolo pyrimidine analogues. [Click here to view]

Triazolo pyrimidine analogues

Bristol-Myers Squibb research and design illustrated in Figure 9 (25) Vipadenant and (26) Ciforadenant have [1,2,3] triazolo[5,4-d] pyrimidine core was first introduced for Parkinsonism. It revealed the selectivity towards A_2AR, but it was discontinued due to failure in the phase-2 clinical trial in preclinical cancer immunology research and observed an othosteric binding site. Ciforadenant potently inhibits c AMP in HEK-293 cells at Ic₅₀=17nM and primary human T cells at IC₅₀=70 nM. Ciforadenant suppresses p CREB and restores PERK levels in human cells.

Figure 9. Triazolo pyrimidine analogues. [Click here to view]

2-Oxothiazole analoguei

TEAOS research group developed 2-Oxothiazole, illustrated in Figure 10, as an A_2AR antagonist to target Parkinsonism’s disease, but due to a high adenosine environment, it does not exhibit antagonistic activity. The high dose required for inhibition within the tumor for cancer management [95]. E core was introduced as cAMP inhibition. It also inhibited CREB phosphorylation as a consequence of A_2AR antagonism. 2-Oxothiazole and its analogues (27A, 27B).

Figure 10. Oxothiazole analogue. [Click here to view]

Pyrazole and Benzothiazole analogue

Further researchers from Merck introduce pyrazolo [4,3-e]-1,2,4-triazolo-[1,5-c] pyrimidine analogue illustrated in Figure 11. (28) Preladenant was introduced for Parkinsonism but terminated in phase-3 consequences of failure in efficacy as compared to placebo. The Preladenant result of the phase-1 clinical trial of (NCT0399161) in advanced solid tumor but data did not support at the endpoint thus terminated. Merck has patented three Benzothiazole compounds (14) Tozadenant where nitrogen atom introduced to improve pharmacokinetic properties.

Figure 11. Pyrazole analogue. [Click here to view]

Benzimidazole (Bioisostere replacement of sulphur with nitrogen)

Benzimidazole and its analogue illustrated in Figure 12 have (29), (30), (31), (32), (33), and (34) A_2AR antagonist effects. Benzimidazole analogues (35), (36), and (37) have the isosteric replacement of sulphur with nitrogen as a consequence of a half-life increase. The half-life of benzimidazole analogues further increased with aryl amide replacement. Consequently, the Benzimidazole morpholino group was replaced with heteroaryl, improving pharmacokinetic properties and these compounds as A_2AR inhibitors. These compounds control the secretion of cytokine that is suppressed by adenosine. These compounds have IC₅₀ = 100–1,000 nM range.

Figure 12. Benzimidazole and isosteric replacement analogues. [Click here to view]

Quinoxalines analogue

Quinoxalines from Benzothiazole illustrated in Figure 13 (38), (39), and (40) retained adenosine antagonistic activity and a half-life of more than 2 hours. In Quinoxalines, the analogue aryl group was replaced with tetrahydropyran, consequently decreasing half-life, and the urea side chain was replaced with aryl amide, consequently poor pharmacokinetic properties.

Figure 13. Quinazoline analogue. [Click here to view]

Amino pyrimidines

2,6-Bis(heteroaryl)-4-amino-pyrimidines design illustrated in Figure 14 and introduces Novartis/Palobiopharma as an A_2AR antagonist. The potency of the compound increased by introducing an electron-withdrawing group at position 5 of the pyrimidine ring. (41) Taminadentant (PBF-509) exhibit 25 times more potent antagonism as compared to bis(hetroaryl)-4-amino pyrimidine A_2AR antagonist. (42), (43) Chloro / cyano substitution at fifth position and pyrrolidyl/ethylthiol/trifluoroethoxyl at the sixth position of the bis(heteroaryl)-4-Amino pyrimidine for its antagonist response and it is important for binding to receptor. Furthermore, PBF-509 exhibits a decreased tumor burden in mice with B16-CD73+ tumors. PBF-509 with PD-L1 maintains immune response in tumor-infiltrating lymphocytes in non-small cell lung cancer cases. PBF-509 produced a synergistic anti-tumor effect with immunotherapeutic agents.

Figure 14. Amino pyrimidine analogue. [Click here to view]

Triazine isomers

AstraZeneca, by using computational techniques to design, illustrates in Figure 15 1,3,5-triazines isomers and 1,2,4 triazines isomers as A_2AR antagonists that access ribose pocket (44), (45), (46). AZD4635 was designed by using an SBDD strategy with PDB:6GT3 and decreased tumor growth (50 mg/kg,po,b.i.d) with anti-PDL1 [123].

Figure 15. Triazine analogue. [Click here to view]

Pyrazole linked heterocyclics as a phosphodiesterase inhibitor

Overexpression of PDE-10A was observed in Cancer then, specifically, PDE-10A inhibitors illustrated in Figure 16 (47), (48), (49).

Figure 16. Pyrazole heterocycles. [Click here to view]

CONCLUSION

In cancer life-threatening conditions chemotherapy failure and drug resistance are major emerging areas for researchers. Hypoxia and associated conditions, tumor micro environment, ROS, and immunosuppressant condition. Adenosine receptor and hypoxia significance emphasize above and management of cancer by modulation of pathway mTOR and in immunity by CTLA 4, PD1 Benzothiazole, quinazoline, and pyrimidine analogue have prominent inhibitory responses in adenosine sites. Alkylating agents exhibit prominent effects in hypoxic tumors and drug response. Thus, design Nitrogen-containing heterocyclic, Benzothiazole, quinazoline pyrimidine analogue have both alkylating and adenosine inhibitory action.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

FINANCIAL SUPPORT

There is no funding to report.

CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included in this research article.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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