Pain is affects approximately 66% cancer patients ⁴³, distressing or intolerable in more than one‐third of patients ⁴⁴ and chronic pain is associated with primary cancer itself or metastases or its treatment (chronic post-cancer treatment pain) ^{43, 44, 45, 46}. Although, WHO described opioids as essential medicines for pain control but distribution shows substantial inequity, a less than 20% of the world’s population consuming more than 90% of the world’s supply ⁴⁶. Also, some 85% of PCPs perceived their training in pain management to be inadequate in a Pan-European survey ⁴⁷. Along with these, fear of dependence, prescription diversion, regulatory scrutiny, withdrawal symptoms, opioid-related adverse events and deaths limit its use ⁴⁶, ^{48, 49, 50, 51, 52}. There is a lack of high-quality evidence regarding the analgesic efficacy of NSAIDs in cancer; contradiction and inconsistent findings also reported ^{53, 54}, although advocated as a useful adjunct for management of cancer pain ^{55, 56}. In addition, long-term use of NSAIDs is often associated with many serious cardiovascular, gastrointestinal, renal, and other side effects ⁵⁴, ⁵⁷. Some other studies also reveal association of NSAIDs with certain cancer types ^{58, 59}. Several studies support use of cannabis/marijuana in cancer pain management ^{60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70}. Its social acceptability is gradually increasing around the world ⁷¹, but many studies oppose it’s use or at least demand further investigation of benefit risk ratio ^{72, 73, 74, 75, 76, 77, 78, 79, 80}. Chemotherapy and radiotherapy are still commonly conventional approaches for treatment of patients harboring advanced cancer ⁸¹. Traditional chemotherapy also associated with neuropathic pain ⁸², fatigue and sleep disturbance ⁸³, anxiety and depression ⁸⁴, mouth sores, nausea and vomiting, early satiety ⁸⁵, alopecia ⁸⁶, bone and muscle wasting ³¹, ⁸⁷. Futile medication use in management of terminally ill cancer patients has also been reported, one-fifth of cancer patients at the end of their life took futile medications (statins and antidementia drugs in nearly 100% cases, antihypertensives and bisphosphonates in nearly 30% cases) ⁸⁸. The goal of cancer palliative care is to prevent or treat, the symptoms and side effects of the cancer type and its treatment, caregiving to any related physical, emotional, social, and spiritual aspects ^{89, 90, 91}. Some alternative therapies, like acupuncture, physical therapy, aromatherapy, CBT are widely recommended along with mind-body interventions like yoga, tai chi, meditation and mindfulness, that keep people fit and energetic as they undergo treatment ^{1, 2}.

Medicinal plants are a rich source of secondary metabolites with interesting biological and pharmacological activities ⁹². Kuruppu et.al, 2019 reported that there are 3000 plants possess some anticancer properties and nearly 75% cancer drugs are derived from natural sources, 40% of them are FDA approved ^{93, 94, 95, 96, 97}. Only a small number of natural anti-tumor products including vinblastine, vincristine, podophyllotoxin, paclitaxel (Taxol) and camptothecin have been tested clinically, while vinflunine ditartrate, anhydrovinblastine, NK-611, tafluposide, paclitaxel poliglumex, combretastatins, salvicine, curcumin, indirubin, triptolide, homoharringtonine are still on trial ⁹⁸. In addition, there are 195,000 pharmacologically active compounds for which the interactions are quantitatively known ⁹⁹. According to an estimate, more than 300,000 secondary metabolites exist in nature ¹⁰⁰. Glycosides ⁹², alkaloids, polyphenols, saponins, tannins and terpenoids ¹⁰¹ have shown promising results in cancer research. Chinese herbal medicines (CHM) also have been demonstrated to exert synergistic effects with other anticancer drugs, improved efficacy and reduced side effects ^{81, 102, 103, 104, 105, 106, 107, 108, 109, 110}. It is an independent medical profession in Hong Kong and mainland China ¹⁰⁸. Cancer patients used CHM to improve their physical and emotional well-beings and to reduce cancer therapy-induced toxicities ¹¹¹. Nutrition and foods are related to about 30% of all the cancers cases ¹¹². Omega-3s from fish pack a stronger punch than other oils when it comes to cancer prevention ^{113, 114, 115}. Seaweeds are specifically used to treat tumors in CHM ¹¹⁶. Several studies revealed that active metabolites among the terpenoids, including carotenoids, polyphenols and alkaloids that can obtained from marine source ^{117, 118, 119, 120, 121, 122, 123, 124, 125}. Compounds from natural sources with anti-proliferative activity represent an important and novel alternative to treat several types of cancer.

American Cancer Society estimated that in 2018 lung and bronchus cancers would be responsible for 234,030 new cases which represent 14% of all new cancer cases and 154,050 deaths ¹²⁶. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 80%-85% of all cases ^{127, 128}. More than half of the NSCLC cases are diagnosed at an advanced stage (stages III and IV) ¹²⁹. Smoking causes at least 80% of lung cancer deaths ¹³⁰. Lin et.al, 2019 concluded association between lung cancer incidence and increased reliance on coal for energy generation ¹³¹. Other possible reasons are exposure to indoor and outdoor air pollution, exposure to radiation, and occupational exposure to agents such as asbestos, nickel, chromium, and arsenic ¹³². Cannabidiol (a non-psychoactive compound from Cannabis sativa), significantly inhibits the recruitment of tumor-associated macrophages (TAM) in primary tumor stroma and secondary lung metastases ¹³³. Table 1.

Figure 1. Alternative Treatment Options 12. One third cancer patients use alternative medicine-are not well regulated and may interact with conventional treatments like chemotherapy and radiation. Some alternative therapies, like acupuncture, physical therapy, aromatherapy, CBT are widely recommended by oncologists for cancer pain management. Mind-body interventions like yoga, tai chi, meditation and mindfulness, which were each used by less than 10% of patients, can keep people fit and energetic as they undergo treatment, reduce the side effects of traditional therapies and improve patients’ sleep, stress and mental health. Many hospitals even have alternative medicine centers that offer these programs.

Figure 2. Plant derived biomolecules studied in lung cancer

Chemotherapy remains the indispensable choice for the vast majority of patients with advanced NSCLC, including primary tumors and lung metastases ¹⁶⁸, ¹⁷¹. Use of the pulmonary route is a promising way to decrease the severe systemic toxicities associated with chemotherapy. Inhalation allows the administration of high drug doses directly to lung tumors without prior distribution in the organism ^{172, 173}. However, Bei-Mu, Jie-Geng, and Mai-Men-Dong-Tang are important CHMs that have improved the survival rate ¹⁷⁴. Euphorbia mauritanica and Kedrostishirtella extracts may play a role in inducing cell death in lung cancer cells ¹⁷⁵. Several 2019 reviews reveal fucoidans (sulfated polysaccharide mainly derived from brown seaweed) in lung cancer management. Brown algae like Fucusvesiculosus, Turbinariaconoides, Laminaria japonica (Figure 3g) are reported in inhibition of tumor migration and invasion, apoptosis induction and inhibition lung cancer cell progression respectively ¹⁷⁶. Fucusevanescens, Sargassum sp., Saccharina Japonica was reported to inhibit proliferation and metastasis, and inducing apoptosis in vitro ¹⁷⁷. Undaria pinnatifida acted on ERK1/2 MAPK and p38, PI3K/Akt signaling, F. evanescens increased metastatic activity of cyclophosphamide and showed cytolytic activity of natural killer cells in 2 different studies and F. vesiculosus (Figure 3f) decreased NF-κB in LLC ¹⁷⁸. U. pinnatifida (Figure 3h) was found to show average antitumor and superior efficacy against LLC in review of Misra et.al, 2019 ¹⁷⁹. Sponge alkaloids from Aaptos showed potential in human lung adenocarcinoma A549, from Fascaplysinopsis exerted an anti-proliferative and pro-apoptotic effect in lung cancer, from blue sponge Xestospongia showed apoptosis as well as stimulate anoikis in H460 lung cancer cells in review by Ercolano et.al, 2019 ¹⁸⁰. Polyphyllin D from Paris polyphylla is well known for its induction of endoplasmic reticulum (ER) stress and mitochondria-mediated apoptotic pathways against lung cancer ¹⁸¹. High fish consumption was significantly associated with a decreased risk of lung cancer ^{182, 183}. Possible mechanism could be changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation ¹⁸⁴. However, other studies reveal healthy dietary intake like high fruit, vegetable, soy protein, poultry (white meat), low-CHO, fish oil-containing diets, together with exercise also decline risks of lung cancer among non-smokers ^{185, 186, 187}. Conversely, long-term use of high doses of some supplements, such as retinol, β-carotene, B vitamins, and vitamin E, increase lung cancer risk in current and former smokers ¹⁸⁸. Smokers should continue to avoid β-carotene supplementation ^{189, 190}. When a person stops smoking before the age of 40, they reduce their chances of dying from smoking-related disease by 90% ¹⁹¹. Telephone counseling reduce cost of nicotine replacement therapy (NRT). Again, cessation with intensive telephone counseling and NRT could be over 20% ¹⁸⁶. Also, lung cancer mortality can be reduced by 20% via low dose CT lung cancer screening and treatment of early-stage disease ¹⁹².

Figure 3. Plants studied in lung cancer (3a). Fritillariae Thunbergii (Bei-Mu) (Source: Inner Path)

Figure 3(b). Platycodon grandiflorum (Jie-Geng) (Source: Wikipedia)

Figure 3(c). Ophiopogonis Decoction (Mài-Mén- Dōng-Tāng)

Figure 3(d). Selaginella tamariscina (Spike Moss)

Figure 3(f). Fucus vesiculosus L. (Source: Seaweed Site of M.D. Guiry)

Figure 3(g). Sesbania grandiflora (Humming-bird tree)

Figure 3(h). Undaria pinnatifida (Source: The Marine Life Information Network)

Hematopoietic cancers constitute a diverse group of diseases including leukemias, lymphomas, plasma cell tumors, myelodysplastic syndromes, and mastocytosis. They arise primarily from two categories of immunological cell types, myeloid and lymphoid cells ¹⁹³. AML is the most common form of acute leukemia in adults, accounting for over 80% of all diagnosed acute leukemias ^{194, 195}. Globally, between 1990 to 2018, the number of leukemia cases markedly increased from 297,000 to 437, 033 ¹⁹⁶, accounting for close to 250,000 annual deaths due to AML worldwide ¹⁹⁷. Optimization of post-remission therapies to maintain complete remission and prevent relapse is a major challenge in treating patients with AML ¹⁹⁸. Children with Down syndrome have a 150-fold increased risk of developing AML and 20-fold increased risk of developing ALL ¹⁹⁹. The incidence of ALL is about 3.3 cases per 100,000 children ²⁰⁰. Outcomes for patients with CML have substantially improved due to advances in drug development and rational treatment intervention strategies ²⁰¹. Allowed costs for leukemia patients averaged almost $157,000 in the year after diagnosis, with costs for AML almost tripling that amount, according to a new report from the Leukemia & Lymphoma Society (LLS) ²⁰². Table 2.

Pterostilbene (Figure 4k) (phytoalexin) isolated from grapevine leaves and blueberries, showing no toxicity in humans up to a dose of 250 mg/day ²⁷⁹, increases Fas expression in T-lymphoblastic leukemia cell lines ²⁸⁰. Blueberry extracts exerted anti-AML efficacy and specifically provoked Erk and Akt regulation within the leukemia stem cell subpopulation ²⁸¹. Quercetin (Figure 4l) is a polyphenol partially responsible for the anti-AML efficacy of blueberry extracts. It can augment and focus the anti-AML efficacy of nano-liposomal ceramide (Lip-C6) and other ceramide-based therapeutics ²⁸². Plant Homeodomain Finger 6 (PHF6) is frequently mutated in T-cell ALL (T-ALL), or AML ²⁸³, are present in about 20% of T-ALL that causes self-renewal and hematopoietic recovery after chemotherapy ²⁸⁴. PHF6 mutations have a significant role in leukemia stem cell activity in the pathogenesis of T-ALL ²⁸⁵. PHF2 low expression was significantly associated with leukemia cell proliferation and several poor prognostic indicators in adult ALL patients. By restoring IKAROS function (zinc finger transcription factor encoded by the IKZF1 gene), PHF2 can be promoted through histone modification ²⁸⁶. Sarkar et.al, 2019 depicted plants of West Bengal (bark of Flacourtiaindica, leaves of Madhucalongifolia (Figure 5b) and Prosopis cineraria) (Figure 5c) showed better cytotoxicity in both AML and CML cell lines (HL-60 and K562) ²⁸⁷. Danışman et.al, 2019 reported combination of flavonoids (apigenin, luteolin, 5-desmethyl sinensetin) and imatinib mesylate were able to enhance the cytotoxic effect on K562 cells in CML ²⁸⁸. Fucoidan (complex polysaccharide from brown seaweeds) inhibited proliferation of the SKM-1 AML cell line via the activation of apoptotic pathways and production of ROS ²⁸⁹ and also induced apoptosis in U937 Cells through activation of p38 MAPK and modulation of Bcl-2 Family ²⁹⁰. In another studies, in vitro and in vivo growth suppression ²⁹¹ and enhancement of therapeutic potential of arsenic trioxide and all-trans retinoic acid ²⁹² in acute promyelocytic leukemia cells also reported. Fucoxanthin (Figure 4m) induced apoptosis in human promyelocytic leukemia HL-60 cell ²⁹³, inhibited growth of leukemia cell lines by ROS generation ²⁹⁴, inhibited phosphorylation of ERK1/2 and histone H3, which are direct downstream signaling targets of lymphokine-activated killer T-cell-originated protein kinase (TOPK) ²⁹⁵, increased cytotoxicity against K562 cells and decreased cell proliferation of K562 and TK6 cells in vitro in imatinib and doxorubicin combination ²⁹⁶. Phlorotannins (algal polyphenols) showed antiproliferative activity in vitro against human leukemia THP-1 and U-937 cells ²⁹⁷. Heteronemin (Figure 4n) (a marine sesterterpenoid) effectively down-regulated cytarabine-induced activation of MAPK, AP-1, NF-κB and c-Myc, the down-stream targets of Ras signaling ²⁹⁸. Cichoriumintybus, Rheum ribes, Alhagipseudalhagi and Glycyrrihza glabra (Figure 5a) (Iranian Traditional plants) also showed notable effects on the leukemia cell lines ²⁹⁹. Juniperus sp. (Figure 5d) can be considered as an alternative source of podophyllotoxin (Figure 4o) and deoxypodophyllotoxin ³⁰⁰.

Figure 4. Plant derived biomolecules studied in leukemias

Figure 5. Plants studied in leukemias (a). Glycyrrhiza glabra (Licorice)

Figure 5(b). Madhuca longifolia (Mahua/Madhuca) (Source: Useful Tropical Plants - Ken Fern)

Figure 5(c). Prosopis cineraria (Khejri/Shami tree) (Source: Greensouq.ae)

Figure 5(d). Juniperus communis (Common Juniper) (Source: IUCN Red List)

The most common breast cancer type is the invasive ductal carcinoma accounting for 70-80% of all breast cancers diagnosed ³⁰¹. It starts in a milk passage (a duct), breaks through the wall of the duct and invades the tissue of the breast ³⁰². In US, 232,000 new cases of breast cancer were diagnosed ³⁰³ and claimed the lives of 40,290 women ³⁰⁴ in 2015. First-degree relatives of patients with breast cancer have a 2-fold to 3-fold excess risk for development of the disease ³⁰⁵. BRCA1 and BRCA2 are the 2 most important genes responsible for increased breast cancer susceptibility ³⁰⁶. Early breast cancer detection programs depend for effectiveness on the participation rate, which is affected by risk factor awareness ³⁰⁷. Since 1990, between 384,000 and 614,500 breast cancer deaths have been averted due to increased mammography screening and improved treatment ³⁰⁸. However, more than 25% breast cancer is projected to be increased by 2020 ³⁰⁹. Women with breast cancer had a higher risk of developing new comorbidities than women without cancer ³⁰⁶. stressful life ³¹⁰, urban living, mastectomy ³¹¹, lower socioeconomic status ³⁰⁹, ³¹², genetic predisposition, African-American origin, not having children or breastfeeding, early menstruation/late menopause, obesity, alcohol abuse, HRT after menopause, benign breast conditions or having breast proliferation, using contraceptives and exposure to diethylstilbestrol ³¹³, age between 40-60, late age first pregnancy, smoking ³¹⁴, abortion history ³¹⁵ are the associated factors. Distressingly, the 5-year cumulative mortality remains unacceptably high at 50%, primarily due to a late-stage presentation ³¹⁶. Wearing bra is not associated with breast cancer risk ³¹⁷ but wearing (tight) bras for many hours and having breast implants ³¹⁵, ³¹⁸ may have associations. Around 60% of breast cancer mortality occurs in LMICs ³¹⁹. The prevalence costs of breast cancer care in the US in 2010 was $16.5 billion ^{320, 321}, and exceeded $39 billion before 2017 ³²². Table 3.

Figure 6. Plant derived biomolecules studied in breast cancer

Ethanolic extract of Juniperus turbinate was more potent cytotoxic than cisplatin in human breast adenocarcinoma MDA-MB-231 cell lines ³⁵⁷. Juniperusoxycedrus ethanolic extract from needles and berries showed potent cytotoxic effects against two breast cancer cell lines (MDA-MB-468 and MCF-7), with no cytotoxicity towards normal cells (PBMCs) ³⁵⁸. Saturejakhuzistanica (Figure 7a) (Lamiaceae), Casearia Sylvestris (Figure 7b) (Salicaceae), Cedrelopsisgrevei (Rutaceae), Solaniumspirale Roxb. (Solanaceae), carbazole alkaloids, Helichrysumgymnocephalum (Asteraceae), Pituranthostortuosus (Apiaceae), Melaleuca armillaris (Myrtaceae), Rosmarinus officinalis (Lamiaceae), Schinus molle L. and Schinus terebinthifolius Raddi(Anacardiaceae), Erigeron acris L.(Asteraceae), Aquilaria sinensis (Thymelaeaceae), Thymus vulgaris L. (Lamiaceae), Schefflera heptaphylla L. (Araliaceae) showed antiproliferative actions on human MCF-7 breast cancer cells ³⁵⁹. XWL-1-48, a potent orally podophyllotoxin derivative suppress Topo II, induce DNA damage and apoptosis, blocks PI3K/AKT/Mdm2 pathway ³⁶⁰. Alteration of Chk-2 signaling in MCF-7 cells reported with 4'-Demethyl-deoxypodophyllotoxin glucoside isolated from Podophyllum hexandrum(Figure 7c)³⁶¹. Genistein (most abundant and active isoflavone in soy), binds to the FIH-1 binding site of HIF-1α protein and downregulates HIF-1α in breast cancer cell line ³⁶². Individuals with the habit of green tea (due to presence of EGCG) were found to have a negative association with the risk of future breast cancer (significantly increases circulating estradiol) ^{363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373}. Compared with the US and EU, some Asian countries like China and Japan have lower breast cancer ³⁶⁴, where dietary consumption of soy products is much higher than US and EU ³⁷⁴. Brown seaweed fucoidan inhibited human breast cancer progression by upregulating microRNA (miR)-29c and downregulating miR-17-5p, thereby suppressing their target genes ³⁷⁵. Lophocladia sp (Lophocladines), Fucus sp (fucoidan), Sargassum muticum (7f) (polyphenol), Porphyra dentata (sterol fraction), Cymopoliabarbata (Figure 7e) (CYP1 inhibitors), Gracilariatermistipitata was found to be effective in breast cancer studies ³⁷⁶. High Urokinase-type plasminogen activator receptor (uPAR) expression predicts for more aggressive disease in several cancer types ³⁷⁷, dietary seaweed may help lowering breast cancer incidence by diminishing levels of uPAR ³⁷⁸. The tropical edible red seaweed Eucheuma cottonii L. (Figure 7d) is rich in polyphenols that exhibited strong anticancer effect with enzyme modulating properties ³⁷⁹. Jazzara et.al, 2016 concluded that λ-carrageenan (Figure 6f) (sulfated galactans found in certain red seaweeds) could be a promising bioactive polymer ³⁸⁰, showed a remarkable inhibitory effect on MDA-MB-231(triple negative breast cancer cell line) cell migration ³⁸¹. Several studies support polyphenols ^{382, 383, 384, 385, 386}, flavonoids ^{387, 388, 389, 390, 391, 392, 393, 394, 395}, fucoidan ^{396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407}, lutein/zeaxanthin ^{408, 409, 410, 411, 412}, other seaweed alkaloids, peptides, tannins and polysaccharides ^{413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425} in breast cancer management.

Figure 7. Plants studied in breast cancer (a). Satureja khuzistanica (Source: Med P Group)

Figure 7(b). Casearia Sylvestris (Source: Árvores do Bioma Cerrado)

Figure 7(c). Podophyllum hexandrum (Source: Wikimedia Commons)

Figure 7(d). Eucheuma cottonii (Source: tradekey.com)

Figure 7(e). Cymopolia barbata (Source: Melev's Reef)

Figure 7(f). Sargassum muticum (Source: Seaweed.ie)

Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of cancer death ⁴²⁶. It is the second leading cause of death in US, affecting some 135,000 estimated new patients with more than 50000 deaths every year ^{427, 428, 429}. In 2015, there were 376,000 new cases and 191,000 deaths in China ⁴³⁰. The overall incidence of CRC is decreasing in many high-income countries, although reported significant increase in Denmark, New Zealand, Australia, UK and Canada, mainly driven by increases in distal (left) tumors of the colon and predominant in ^{431, 432, 433, 434, 435, 436, 437, 438}. Lifestyle determines around 50% to 60% incident of CRC irrespective of age ^{439, 440, 441, 442}. Physical activity may prevent approximately 15% of the colon cancers ⁴⁴³. Fish, poultry, cheese, fruit, vegetables, tea and coffee were not associated with colorectal-cancer risk ⁴⁴⁴. Alcohol consumption, red meat/processed meat, junk food, smoking, diabetes and obesity potentiate the same risk ^{445, 446, 447, 448}. In 2018, the estimated national expenditure was $16.6 billion in US, which was $4.5 billion to $9.6 billion in 2009 and projected to be more than $20 in 2020 ^{449, 450, 451}. There were over 1.8 million new cases in 2018. Hungary, North Korea, Slovakia, Norway, Denmark, Portugal, Japan are in the top-ranking positions ⁴⁵². 5-year survival for patients with stage IV CRC is less than 10% ⁴⁵³. The overall risk of CRC among patients with ulcerative colitis is about ten times higher than that of the general population ⁴⁵⁴. A recent study reveals that chili peppers does not increase or decrease the risk of CRC ⁴⁵⁵. Previous studies say capsaicin has both carcinogenic and anticancer effects. Table 4.

Aloe-emodin, a natural compound extract from Aloe Vera, has been discovered to suppress cell proliferation and accelerate apoptosis in a variety of tumor cells ⁵¹⁴. Camptothecin induces the upregulation of Programmed Death-Ligand 1(PD-L1) and other cytokines that modulate the attraction, migration, and functions of immune cells, primarily T-cells ⁵¹⁵. Scutellarin (Figure 8m) is a flavonoid isolated from a medicinal herb Scutellariabarbata(Figure 9a), downregulates the anti-apoptotic protein Bcl-2 and induces apoptosis by activating p53, which upregulates Bax to activate caspase 3 via the mitochondrial pathway ⁵¹⁶. Treatment of HT-29 cells with luteolin (flavonoid, exist in fruits, vegetables and medicinal herbs) results in a loss of the mitochondrial membrane potential, an increase in mitochondrial Ca2+ level, upregulation of Bax, downregulation of Bcl-2, release of cytochrome c from the mitochondria to the cytosol and an increase in the levels of the active forms of caspase-9 and caspase-3 ⁵¹⁷. Treatment of Caco-2 CRC cells with extra virgin olive oil (rich in hydroxytyrosol and oleuropein) miR-23a and miR-301a, which were predicted to target type 1 cannabinoid receptor (CB1) in colon cancer ⁵¹⁸, important implications in chemoprevention. Gambogic acid (Figure 8n), a xanthonoid extracted from the resin of Garcinia hanburyi (Figure 9b) inhibits HT-29 proliferation via induction of apoptosis ⁵¹⁹. Walnuts (genus Juglans) have been shown to suppress colon cancer in mice models through the decreased expression of miR-1903, miR-467c, and miR-3068, as well as the increased expression of miR-297a in athymic nude mice injected subcutaneously with HT-29 CRC cells ⁵²⁰. Also, Aggarwal et.al, 2013 listed phytochemicals like garcinol, gossypol, gossypin, guggulsterone, indole-3-carbinol, morin, naphthoquinone, nimbolide, noscapine, oleandrin, piperine, piceatannol, pinitol, plumbagin, pomegranate, retnoids, honokiol, sesamin, silymarin, simvastatin, terpenoid, thymoquinone, tocotrienol, triptolide, ursolic acid, withanolides, xanthohumol, and zerumbone ⁴⁵⁸ having potentials in CRC. Seaweeds like U. pinnatifida¹⁷⁵, ⁴⁰¹, ^{521, 522, 523, 524, 525, 526, 527}, Saccharina latissimi (9c) ⁵²⁸, Fucusvesiculosus¹⁷⁶, ²⁹⁵, ^{529, 530}, Sargassum hemiphyllum (Figure 9d) ^{531, 532, 533} have proven efficacy in this situation. Also, Algae derived astaxanthin ^{534, 535, 536, 537, 538, 539, 540}, fucoxanthin ^{541, 542, 543, 544, 545}, lutein and zeaxanthin ^{546, 547, 548, 549}, polyphenols ^{550, 551, 552, 553, 554} shown individual excellence.

Figure 8. Plant derived biomolecules studied in colorectal cancer

Figure 9(a). Scutellaria barbata (Source: Strictly Medicinal Seeds)

Figure9(b). Garcinia hanburyi (Source: Vitamin Supplement Ingredients Information)

Figure 9(c). Saccharina latissimi (Source: Nature Picture Library Print Store)

Figure 9(d). Sargassum hemiphyllum (Source: natural-history.main.jp)

Caffeic acid phenethyl ester (Figure 10a) is a central active component of propolis from honeybee hives. Propolis is a well-known health supplement that is extremely popular in Australia and New Zealand. It is constantly marketed in Japan with sales exceeding US$300 million/year ⁵⁵⁵. It can impart strong antimitogenic activity in lung cancer, breast cancer ⁵⁵⁶ and apoptosis in colon cancer ⁵⁵⁷. Peripheral neuropathy is a common side effect of many chemotherapeutic agents including paclitaxel. Poor nutritional status and obesity increase the risk of paclitaxel induced neuropathy ⁵⁵⁸. PEGylated liposomes of paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo ⁵⁵⁹. Glutathione ⁵⁶⁰ and gallic acid ⁵⁶¹ may ameliorate paclitaxel-induced neuropathic pain. Di(2-ethylhexyl) phthalate (DEHP) (Figure 10b), estrogen receptor alpha (ERα) agonist due to its ability to interact with ERα and promote the cell proliferation of ERα-positive breast cancer cells, significantly protected MCF-7 cells against the genotoxicity of camptothecin ⁵⁶². Actinomycin D obtained from various Streptomyces strains decreases Mcl-1 expression in lung cancer cells ⁵⁶³, induces p53-independent cell death in leukemia ⁵⁶⁴, synergistically suppressed multiple metastasis of TRAIL-resistant colon cancer in the liver with soluble TRAIL gene ⁵⁶⁵. Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin and mitomycin C (Figure 10c) (obtained from Streptomyces caespitosus) is the only protocol to demonstrate an adjuvant HIPEC benefit in colorectal cancer patients at high risk for peritoneal failure and an alternative to high-dose and short-term oxaliplatin ⁵⁶⁶. 5-FU plus mitomycin remains the preferred chemotherapy in most patients with anal cancer ⁵⁶⁷. Bleomycin (Figure 10e) is an antibiotic complex of several glycopeptides derived from Streptomyces verticillus, gained FDA approval in July 1973. The extract from Streptomyces sp. MUM265- represents a valuable bioresource of bioactive compounds for the future development of chemo-preventive agents, with particular promise suggested for treatment of colon cancer ⁵⁶⁸. Bleomycin is an indispensable antineoplastic agent for the treatment of germ cell tumors and lymphomas. Pirfenidone (Figure 10d) (novel orally available antifibrotic drug approved by the FDA in 2014) is currently the only approved therapy for idiopathic pulmonary fibrosis (IPF), considered as a salvage drug for refractory cases of bleomycin-induced lung injury ⁵⁶⁹. In a similar study, Yu et.al, 2019 reported EZY-1 (16-amino-acid peptide was isolated from Eucheuma) can inhibit the IPF induced by bleomycin ⁵⁷⁰.

Figure 10. Biomolecules from non-plant origin studied or used in different types cancers

According to the Global Health Observatory Report from the WHO, insufficient physical activity is the 4th leading risk factor for mortality. Participation in 150 minutes of moderate physical activity a week or its equivalent is estimated to reduce risk of breast and colon cancer by 21%–25% ⁵⁷¹. Approximately 50% of all leukemia, lymphoma, colorectal- and breast cancer patients are affected by CIPN. Sensorimotor training (SMT) or whole-body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits ⁵⁷². Hypnosis, music (Figure 11) and relaxing video reduced anxiety and pain associated with colonoscopy and need for sedation during colon cancer screening ^{573, 574, 575, 576, 577, 578, 579, 580, 581}. Impaired cognitive function, change in brain metabolism and change in brain structure are associated with cancer treatment. CBT moderately improved anxiety and depression in patients with early-stage breast cancer ⁵⁸², significantly improved tumor associated fatigue levels after 8 weeks ⁵⁸³, improved QoL ⁵⁸⁴, improved cognitive function ⁵⁸⁵, improved insomnia ^{586, 587}, reduced fear of cancer recurrence ⁵⁸⁸ and most importantly, reduced pain and distress ⁵⁸⁹. Mindfulness-based approaches and hypnosis reduced demonstrated efficacy in reducing anxiety and depressive symptoms. 40% to 50% CRC patients reported fear of cancer recurrence, tends to increase around the time of scans or other testing for recurrence ⁵⁹⁰. Also, CRC patients have unique psychosocial needs (e.g., isolation, embarrassment) related to altered eating and bowel habits and sexual dysfunction that warrant clinical attention ⁵⁹¹. Acceptance and commitment therapy, meta-cognitive therapy, and mindfulness-based therapies emphasize mindfulness, acceptance, cognitive flexibility, and patient values changes in self-efficacy or confidence in using coping skills targeted by the intervention, acceptance of unwanted thoughts and feelings, or enhanced social support as well as physiological mechanisms (e.g., decreased arousal to negative thoughts and feelings about cancer) ⁵⁹². Combined CBT/GET improves fatigue and functional outcomes for a subset of patients with post-cancer fatigue in breast or colon cancer ⁵⁹³. CBT intervention has the potential to ease acute anxiety during the often-challenging re-entry phase and to prevent the development of chronic, debilitating, and costly anxiety ⁵⁹⁴. Physical activity interventions also reduce depressive and anxiety symptoms in breast cancer survivors ⁵⁹⁵. Telehealth approaches may improve access to mental health resources especially for those with limited online access or lack of online skill ⁵⁹⁶. Yoga has a solid effect on cancer-related fatigue in patients with breast cancer ⁵⁹⁷. It is one of the most prevalent complementary therapies used in breast cancer care, seems to be as effective as other exercise modalities for improving the QoL of women with breast cancer ⁵⁹⁸. Wei et.al, 2019 reported significant improvement in lymphedema status, range of shoulder motion and spinal mobility after an 8-week yoga intervention ⁵⁹⁹. Although, yoga could not improve HRQoL in patients with colorectal cancer ⁶⁰⁰ but research supports that yoga is a promising intervention for reducing fatigue and sleep disturbances in this patient group ⁶⁰¹.

Figure 11. Music Therapy: Pain or Distress Management 619. In the UK, music therapists are trained to master’s level and are registered with Health and Care Professions Council as allied health professionals. Aristotle recognized the innate ability of melodies to surpass “feelings such as pity and fear, or enthusiasm,” and thus “heal and purify the soul.” The Greeks identified Apollo as the father of both healing and music, alongside his many other accolades (as God of light, sun, truth, prophecy, plague and poetry).

Dyadic yoga may offer effective relaxation techniques for lung cancer patients and their caregivers who were undergoing an extreme stressor in addition to the cancer experience ⁶⁰², feasible and beneficial for patients having toxic thoracic radiography ⁶⁰³. Approximately 20% of breast cancer survivors develop breast cancer-related lymphedema (BCRL) ⁶⁰⁴. Acupuncture is safe and effective at reducing breast cancer-related lymphoedema in patients after breast cancer treatment ⁶⁰⁵ and managing joint stiffness. Acupuncture use among breast cancer patients in the US is currently as high as 16% to 63% ⁶⁰⁶. At the current time breast cancer related lymphedema is incurable but well manageable by a number of physical therapy modalities, especially complete decongestive therapy (CDT) ⁶⁰⁷. Obesity is a factor that deteriorates the CDT efficacy. Early treatment, before developing fat accumulation and fibrosis, must be primary goal in the treatment of BCRL ⁶⁰⁸. The first “intensive treatment” phase aims to decongest the swollen arm through two or more weeks of daily therapist-delivered treatment including multi-layer compression bandaging and manual lymph drainage (MLD). This is followed by a “maintenance” phase of patient self-treatment, with compression usually in the form of hosiery ⁶⁰⁹. The mindfulness component may enhance the positive impact of exercise on cognitive function in breast cancer ^{610, 611}. Tai Chi is accessible to most people and does not require special facilities or expensive equipment ⁶¹². Healthier dietary choices were the most frequently reported change already made by people affected by CRC, followed by increased physical activity, stress management, quitting smoking and alcohol and therapies including meditation, tai chi, and naturopathy ⁶¹³. Greater shoulder muscular strength was significantly associated with better functional well-being in breast cancer survivors with TC Qigong training ⁶¹⁴. Massage with or without aromatherapy have been suggested by a few studies in breast cancer to ameliorate anxiety and other symptom relief ⁶¹⁵ and immunologic state ⁶¹⁶ that needs further investigation. TENS was found valuable in lung cancer patient underwent standard posterolateral thoracotomy ⁶¹⁷. Animal-assisted activities (Figure 12) has potential benefit children with cancer because pediatric oncology patients often suffer from distress due to physical examinations, venipuncture, chemotherapy infusions, spinal taps, surgery, hospitalization, pain, fear of medical procedures, unpleasant physical symptoms, uncertainty, and worry about death ⁶¹⁸.

Figure 12. Hospitalized kid on animal visit 620. Understanding whether AAA is safe and effective for pediatric cancer patients is critical, especially because of concern about infection in immunosuppressed persons. Conducting AAA research in pediatric oncology requires understanding current regulations and variations in practice. Knowledge of regulations helps us understand elements required for intervention protocols (e.g., hand-cleaning), whereas knowledge of practice variation can help us identify research opportunities.